Fact-checked by Grok 2 weeks ago

TMPRSS2

TMPRSS2 (transmembrane protease, serine 2) is a human protein-coding gene that encodes a type II transmembrane serine protease belonging to the serine protease family, featuring a type II transmembrane domain, a low-density lipoprotein receptor class A domain, a scavenger receptor cysteine-rich domain, and a serine protease domain.^[1] The gene is located on the long arm of chromosome 21 at cytogenetic band 21q22.3.^[2] The encoded TMPRSS2 protein possesses a catalytic triad composed of histidine 296, aspartate 345, and serine 441, enabling its proteolytic activity.^[3] TMPRSS2 is highly expressed in prostate epithelial cells, where its transcription is androgen-responsive, contributing to normal prostate physiology through participation in proteolytic cascades.^[4] It also plays a critical role in the pathogenesis of certain enveloped viruses by priming their surface glycoproteins for membrane fusion and cell entry; for instance, TMPRSS2 cleaves the spike protein of SARS-CoV-2 at multiple sites, facilitating viral infection of airway epithelial cells in conjunction with ACE2 receptor binding.^[5]^[3] Similarly, TMPRSS2 activates the hemagglutinin of influenza A viruses, promoting viral spread in the respiratory tract.^[6] In oncology, TMPRSS2 is frequently fused with ETS family transcription factors like ERG due to genomic rearrangements, a event occurring in approximately 50% of prostate cancers and driving tumor progression through aberrant activation of oncogenic pathways.^[7] Recent structural studies have elucidated TMPRSS2's zymogen activation and substrate recognition mechanisms, informing potential therapeutic targeting for both viral infections and malignancies.^[8]

Discovery and History

Initial Cloning and Identification

The TMPRSS2 gene was initially cloned in 1997 through a systematic exon-trapping approach targeting human chromosome 21q22.3, as part of efforts to identify novel transcripts in genomic regions associated with genetic disorders.^[9] Researchers led by Antonarakis and colleagues used selected trapped exons to isolate and characterize the gene, which encodes a predicted multimeric protein featuring a serine protease domain alongside transmembrane, low-density lipoprotein receptor A (LDLRA), and scavenger receptor cysteine-rich (SRCR) domains.^[9] This identification marked TMPRSS2 as a member of the type II transmembrane serine protease (TTSP) family, distinguished by its integral membrane topology and potential proteolytic function.^[10] The cloning process involved screening a genomic library from chromosome 21, followed by cDNA synthesis and sequencing to confirm the open reading frame spanning approximately 3.5 kb, with the protease domain exhibiting homology to other serine proteases like hepsin.^[9] Northern blot analysis subsequently revealed TMPRSS2 expression predominantly in prostate epithelial cells, suggesting a role in glandular physiology, though initial studies did not elucidate its substrates or activation mechanisms.^[9] The gene's localization to 21q22.3 was verified through fluorescence in situ hybridization (FISH), positioning it near loci implicated in amyotrophic lateral sclerosis and other conditions, though no direct pathogenic links were established at the time.^[9]

Key Research Milestones

The TMPRSS2 gene was cloned in 1997 by Paoloni-Giacobino et al. through exon-trapping methods, identifying it as a novel type II transmembrane serine protease with a transmembrane domain, low-density lipoprotein receptor A (LDLRA) domain, scavenger receptor cysteine-rich (SRCR) domain, and a serine protease domain, localized to human chromosome 21q22.3.^[9] In 1999, Lin et al. demonstrated that TMPRSS2 mRNA expression is strongly induced by androgens in LNCaP prostate cancer cells, establishing its androgen-responsive regulation in prostatic tissue.^[11] In 2005, Tomlins et al. identified recurrent gene fusions between TMPRSS2 and ETS transcription factors, particularly ERG, in approximately 50% of prostate cancers, marking a major advance in understanding prostate cancer genomics and TMPRSS2's role in oncogenic rearrangement. This fusion results from interstitial deletions or translocations, driving aberrant ERG expression under androgen control and associating with tumor initiation and progression in fusion-positive cases.^[12] TMPRSS2's involvement in viral pathogenesis emerged in 2006, when Böttcher et al. showed it facilitates influenza A virus spread by cleaving the viral hemagglutinin protein in airway cells, enabling membrane fusion and entry.^[10] In 2010, Matsuyama et al. reported that TMPRSS2 activates the SARS-CoV spike protein for cell entry in vitro, highlighting its broader role in coronavirus priming.^[13] A pivotal milestone occurred in 2020 amid the COVID-19 pandemic, when Hoffmann et al. demonstrated that SARS-CoV-2 cell entry requires TMPRSS2-mediated priming of the viral spike protein alongside ACE2 receptor binding, with inhibition by camostat mesylate blocking infection in lung cells.^[14] This finding spurred research into TMPRSS2 as a therapeutic target, linking its prostate cancer associations to antiviral strategies via androgen deprivation or protease inhibitors.^[15] Subsequent studies confirmed TMPRSS2's necessity for efficient SARS-CoV-2 replication in human airways, influencing variant tropism and innate immune responses.^[16]

Gene Characteristics

Genomic Structure and Location

The TMPRSS2 gene is located on the long (q) arm of human chromosome 21 at cytogenetic band 21q22.3.^[1] In the GRCh38.p14 primary assembly of the human reference genome, the gene spans genomic coordinates 41,464,305 to 41,508,158 on the complementary (reverse) strand, encompassing a total length of 43,854 base pairs.^[1] This positioning places TMPRSS2 in proximity to genes such as ERG, facilitating recurrent gene fusions observed in prostate cancer.^[17] The gene structure consists of 15 exons, with protein-coding sequences predominantly in the exons toward the 3' end.^[1] Multiple transcript variants arise from alternative splicing, including the reference transcript NM_005656.4 (isoform 2, encoding a 492-amino-acid protein) and the longest isoform NM_001135099.1.^[1] The 5' untranslated region includes regulatory elements, such as a 15-base-pair androgen response element located 148 base pairs upstream of the transcription start site, though this pertains more to expression regulation.^[18] Ensembl annotations identify 40 transcripts for TMPRSS2, reflecting splicing complexity, with the canonical transcript ENST00000332149 featuring protein-coding exons that align with the serine protease domain architecture.^[19]

Expression Patterns and Regulation

TMPRSS2 mRNA exhibits its highest expression levels in the prostate gland among normal human tissues, with substantial expression also detected in the lungs, pancreas, stomach, small intestine, and salivary glands.^[20] In the respiratory tract, TMPRSS2 is prominently expressed in small airway epithelial cells and nasal epithelium, contributing to its role in viral entry at these sites.^[21] Lower but detectable levels occur in other organs, including the kidney, colon, liver, and gastrointestinal tract, while expression is minimal in tissues such as the brain and heart.^[22] ^[23] At the cellular level, TMPRSS2 localizes primarily to epithelial cells, including prostate luminal epithelium, bronchial epithelial cells, and subsets of oral and nasopharyngeal mucosa such as basal, apical, goblet, and ciliary cells.^[24] Gene expression datasets indicate that TMPRSS2 transcripts are more abundant in male prostate and lung tissues compared to females, aligning with its androgen sensitivity, though widespread expression persists across sexes in non-reproductive organs.^[20] ^[25] TMPRSS2 expression is predominantly regulated by androgens via androgen receptor (AR) binding to responsive elements in its promoter and a critical enhancer region approximately 13 kb upstream of the transcription start site.^[26] This mechanism drives high prostate-specific upregulation, as evidenced by inclusion in AR-regulated gene cohorts alongside markers like KLK3 (PSA) and NKX3.1.^[27] Androgen deprivation therapies, including enzalutamide, suppress TMPRSS2 levels in prostate-derived cells, reducing viral priming capacity, but exert weaker effects in lung cells and organoids, implying additional tissue-specific regulators such as non-AR transcription factors.^[28] ^[29] Limited evidence suggests estrogen-mediated modulation in certain contexts, though androgen control remains dominant.^[30]

Protein Structure and Mechanism

Molecular Architecture

The TMPRSS2 protein is a 492-amino-acid type II transmembrane serine protease characterized by a short N-terminal cytoplasmic domain (residues 1-26), a single-pass transmembrane helix (residues 27-49), and an extensive extracellular ectodomain.^[31] ^[32] The ectodomain includes a stem region comprising a low-density lipoprotein receptor class A (LDLRA) domain (residues 111-150) and a scavenger receptor cysteine-rich (SRCR) domain (residues 152-247), followed by the C-terminal serine protease (SP) domain (residues 256-492).^[3] ^[33] These non-protease domains in the stem region contribute to substrate recognition and localization, with the SRCR domain implicated in interactions such as binding to viral spike proteins or bacterial toxins.^[34] ^[35] The SP domain adopts a chymotrypsin-like fold typical of S1 family serine proteases, featuring a catalytic triad composed of His296, Asp345, and Ser441, which facilitates nucleophilic attack on peptide bonds, preferentially cleaving after arginine residues.^[3] ^[8] Crystal structures of the TMPRSS2 protease domain, such as PDB entry 7MEQ, reveal an active site with a narrow S1 pocket dominated by Asp435, conferring trypsin-like specificity, and conserved loops that modulate inhibitor access.^[36] ^[37] TMPRSS2 is synthesized as an inactive zymogen, undergoing autocatalytic activation via cleavage between Arg255 and His256, which removes an intervening propeptide segment and exposes the mature protease domain for membrane-anchored activity.^[8] ^[38] Post-translational modifications, including N-linked glycosylation at Asn133 and Asn162 in the stem region, influence folding, stability, and cell surface trafficking, while the absence of disulfide bonds in the cytoplasmic tail underscores its regulatory role in endocytosis or signaling.^[39] The overall architecture positions the protease domain extracellularly, enabling cleavage of membrane-bound substrates like viral glycoproteins or receptors such as ACE2.^[25]

Catalytic Function and Activation

TMPRSS2 exhibits trypsin-like serine protease activity, preferentially cleaving peptide bonds C-terminal to basic residues such as arginine and lysine.^[40] This specificity enables it to process a range of substrates involved in extracellular matrix remodeling and viral glycoprotein activation.^[3] The enzyme's catalytic mechanism relies on a conserved triad comprising histidine 296 (H296), aspartate 345 (D345), and serine 441 (S441), which facilitates nucleophilic attack by the serine hydroxyl group on the substrate carbonyl carbon, forming a tetrahedral intermediate and enabling peptide bond hydrolysis.^[35] ^[8] As a type II transmembrane serine protease, TMPRSS2 is initially synthesized as an inactive zymogen with an N-terminal prodomain masking the active site.^[8] Activation proceeds via autocatalytic cleavage at the Arg255-Ile256 peptide bond within the zymogen activation motif, which removes the inhibitory propeptide and exposes the mature catalytic domain.^[41] This intramolecular proteolysis is initiated by low-level catalytic activity of the zymogen form, occurring intracellularly in compartments such as the endoplasmic reticulum or Golgi apparatus, prior to trafficking to the plasma membrane.^[42] The resulting active enzyme remains anchored to the cell surface via its transmembrane domain, with the ectodomain protease tethered by disulfide bonds.^[3] Structural studies reveal that the activation loop in the zymogen adopts a conformation that positions Arg255 for cleavage by the catalytic triad, with subsequent conformational changes stabilizing the active site oxyanion hole formed by Gly438 and Ser440.^[8] Inhibition of this autocatalytic step, as demonstrated by mutations like S441A, prevents maturation and abolishes proteolytic function, underscoring its essential role in enzyme competency.^[3] Once activated, TMPRSS2's activity is regulated by endogenous inhibitors such as hepatocyte growth factor activator inhibitor-1 (HAI-1), which forms complexes to limit uncontrolled proteolysis.^[40]

Physiological Roles

Proteolytic Substrates and Pathways

TMPRSS2, a type II transmembrane serine protease, preferentially cleaves peptide bonds following arginine residues at the P1 position, with additional specificity influenced by residues at P2–P4 positions.^[43] Its proteolytic activity is initiated through autocleavage of the zymogen form, exposing the active site for substrate processing.^[8] In physiological contexts, TMPRSS2 activates several endogenous substrates, particularly in prostate epithelial cells where it is highly expressed. It processes pro-hepatocyte growth factor (pro-HGF) into mature HGF, which binds the MET receptor to promote cell proliferation, motility, and survival via downstream signaling pathways such as PI3K/AKT and MAPK/ERK.^[44] TMPRSS2 also activates the zymogen form of matriptase (ST14), a related serine protease, initiating a proteolytic cascade that enhances extracellular matrix remodeling and epithelial-mesenchymal transition (EMT) through further activation of substrates like urokinase plasminogen activator (uPA).^[45] Additionally, TMPRSS2 cleaves protease-activated receptor-2 (PAR-2/F2RL1), triggering G-protein-coupled signaling that modulates inflammation and tissue remodeling, and degrades extracellular matrix components such as nidogen-1 and laminin, facilitating cell migration in glandular tissues.^[46] These actions contribute to normal prostate function, including prostasome-mediated processes in seminal fluid, though direct roles in semen liquefaction or fertility remain under investigation.^[4] Beyond endogenous proteins, TMPRSS2 processes viral glycoproteins in respiratory epithelia, cleaving the hemagglutinin (HA) of influenza A and B viruses at monobasic sites to enable membrane fusion and viral spread.^[47] For coronaviruses, it cleaves the SARS-CoV-2 spike protein at the S2' site after initial furin processing, promoting direct fusion of viral and host membranes independent of endosomal entry.^[3] This surface pathway contrasts with cathepsin-mediated endosomal activation, with TMPRSS2 dependency varying by viral variant; for instance, Omicron shows reduced reliance on TMPRSS2 compared to earlier strains.^[48] Inhibition of these cleavages blocks viral entry, highlighting TMPRSS2's role in airway infection pathways.^[49]

Androgen-Dependent Expression

TMPRSS2 expression is strongly regulated by androgens via the androgen receptor (AR) in prostate epithelial cells, particularly in the luminal secretory compartment where it is predominantly localized.^[50] This regulation occurs through AR binding to specific androgen response elements (AREs) within an enhancer region approximately 13 kilobases upstream of the TMPRSS2 transcription start site, which is essential for androgen-inducible transcription.^[26] Adjacent to this ARE are binding sites for the pioneer factor GATA2, facilitating chromatin accessibility and cooperative enhancement of AR-mediated activation.^[50] In normal prostate physiology, androgen stimulation, such as by dihydrotestosterone, induces TMPRSS2 transcription as part of a broader program of AR-responsive genes, including prostate-specific antigen (KLK3/PSA) and NKX3.1, supporting epithelial differentiation and secretory functions.^[27] Studies in androgen-dependent prostate xenografts confirm TMPRSS2 upregulation correlates with AR activity, with splice variants showing marked overexpression under androgen influence.^[51] This dependency underscores TMPRSS2's role in androgen-driven prostate homeostasis, where its proteolytic activity may process substrates involved in glandular secretion or cell signaling.^[44] Beyond the prostate, androgen regulation of TMPRSS2 extends to other tissues, though at lower basal levels; for instance, pulmonary TMPRSS2 expression shows partial AR dependence in some models, but enzalutamide treatment does not consistently reduce it in male mice, suggesting context-specific modifiers.^[52] In androgen deprivation scenarios, such as therapeutic castration, TMPRSS2 mRNA and protein levels decline significantly in responsive cells, highlighting its utility as an AR target readout.^[53] This regulatory axis persists in pathological states like early prostate cancer but can reactivate in castration-resistant disease through AR reprogramming.^[54]

Disease Associations

Prostate Cancer Involvement

TMPRSS2, encoding a transmembrane serine protease, exhibits high expression in normal prostate luminal epithelial cells, where its transcription is strongly induced by androgen receptor (AR) signaling via direct binding to androgen response elements in its promoter.^[55] In prostate cancer (PCa), TMPRSS2 overexpression persists and correlates with AR activity, contributing to tumor progression through proteolytic cleavage of extracellular matrix components and activation of signaling pathways that promote invasion and metastasis.^[45] Specifically, TMPRSS2 activates the related protease matriptase (ST14), which in turn processes hepatocyte growth factor (HGF) and other substrates, enhancing epithelial-mesenchymal transition and metastatic potential in AR-positive PCa models.^[45] This androgen-dependent proteolytic cascade is evident in localized high-grade tumors and the majority of PCa metastases, where TMPRSS2 mRNA and protein levels are elevated compared to benign tissue.^[44] The most frequent genetic alteration involving TMPRSS2 in PCa is its fusion with ETS family transcription factors, particularly ERG, resulting from interstitial deletion or rearrangement on chromosome 21q22.2-3.^[55] TMPRSS2-ERG fusions occur in 40-50% of primary prostate adenocarcinomas in Western populations, with prevalence estimates of 46% in PSA-screened U.S. cohorts based on fluorescence in situ hybridization analysis of needle biopsies.^[56] ^[57] The fusion places the AR-regulated TMPRSS2 promoter upstream of ERG exons 2-11, driving ligand-dependent ERG overexpression that dysregulates target genes involved in cell proliferation, differentiation, and genomic instability.^[55] TMPRSS2 fusions with other ETS genes (e.g., ETV1, ETV4) are less common, accounting for 5-15% of cases, while non-ETS fusions (e.g., with NCOA4) represent under 5%.^[55] These fusions arise early in PCa pathogenesis, detectable in 10-20% of high-grade prostatic intraepithelial neoplasia (HGPIN) lesions adjacent to TMPRSS2-ERG-positive tumors, suggesting a precursor role.^[58] Functionally, TMPRSS2-ERG promotes oncogenesis by cooperating with factors like PTEN loss or TP53 mutations, though the fusion alone does not transform benign prostate epithelial cells in vitro or induce tumors in mouse models without additional hits.^[59] In vivo, transgenic expression of TMPRSS2-ERG in prostate epithelium accelerates progression in PTEN-heterozygous mice, leading to invasive cancers with increased proliferation and reduced apoptosis.^[60] Prevalence varies by ancestry, with lower rates (e.g., 20-30%) in African and Asian cohorts compared to 50% in Europeans, potentially reflecting differences in androgen exposure or genomic architecture.^[56] ^[61] Prognostically, TMPRSS2-ERG fusion status shows inconsistent associations with outcomes; some cohorts link it to higher Gleason scores and biochemical recurrence risk, while others report favorable responses to androgen deprivation therapy (ADT), with fusion-positive tumors exhibiting lower prostate cancer-specific mortality (hazard ratio 0.64) post-radical prostatectomy and ADT.^[62] ^[12] This may stem from retained AR dependence in fusion-driven tumors, rendering them more sensitive to hormonal manipulation, though fusion-negative PCa often harbors more aggressive alterations like SPOP mutations or PTEN deletions.^[57] Detection of TMPRSS2-ERG transcripts in post-digital rectal exam urine achieves 80% sensitivity and 90% specificity for PCa diagnosis when combined with PCA3, aiding risk stratification.^[63] Overall, TMPRSS2 alterations underscore AR-prostate axis centrality in PCa, with fusions serving as molecular subtypes for precision approaches rather than standalone drivers.^[64]

Viral Pathogenesis

TMPRSS2 facilitates viral pathogenesis primarily by cleaving viral surface glycoproteins, enabling membrane fusion and host cell entry, with expression concentrated in respiratory epithelia making it a key determinant of infection efficiency in the airways.^[3] This serine protease activates enveloped viruses through proteolytic priming at the cell surface, bypassing endosomal pathways and promoting rapid spread, as demonstrated in human airway cell models where TMPRSS2 knockdown significantly impairs multicycle replication.^[65] Its role extends to multiple respiratory pathogens, where inhibition reduces viral titers by 10- to 100-fold in TMPRSS2-expressing cells.^[25]

Coronaviruses Including SARS-CoV-2

TMPRSS2 proteolytically processes the SARS-CoV-2 spike (S) protein at the S2' site, triggering conformational changes that drive fusion of the viral envelope with the host plasma membrane and efficient entry into pneumocytes and bronchial cells.^[3] This surface pathway contrasts with cathepsin-mediated endosomal entry in TMPRSS2-low cells, with TMPRSS2-dependent infection predominant in Calu-3 lung cells and VeroE6/TMPRSS2 transfectants, where viral entry is reduced over 90% upon protease inhibition.^[66] For SARS-CoV and MERS-CoV, TMPRSS2 similarly activates S protein in trans, enhancing pseudovirus infectivity in human airway cultures by up to 50-fold compared to TMPRSS2-null models.^[65] ^[67] Sequential cleavage often involves furin at the S1/S2 boundary followed by TMPRSS2, as evidenced by studies showing TMPRSS2 knockout mice exhibit attenuated SARS-CoV-2 lung pathology and reduced viral loads.^[49] TMPRSS4 can compensate in some contexts, but TMPRSS2 remains the primary activator in TMPRSS2-high respiratory tissues.^[68]

Influenza and Other Respiratory Viruses

In influenza A virus (IAV) infection, TMPRSS2 serves as the predominant activator of hemagglutinin (HA) in primary human bronchial epithelial cells, cleaving HA at monobasic or polybasic sites to expose the fusion peptide and initiate entry, with TMPRSS2 inhibition blocking over 80% of viral spread in air-liquid interface cultures.^[69] This mechanism supports pathogenesis of H1N1, H3, and H7 subtypes, as Tmprss2-deficient mice show restricted viral dissemination in lungs and 100-fold lower titers following intranasal challenge with pandemic H1N1 strains.^[70] Human airway trypsin-like protease (HAT/TMPRSS11B) acts redundantly in some cases, but TMPRSS2 dominates in vivo, with co-expression in target cells like alveolar type II cells amplifying multicycle replication.^[71] For other viruses, such as certain paramyxoviruses, TMPRSS2 contributes to glycoprotein priming, though less critically than for orthomyxoviruses and coronaviruses, underscoring its airway-specific role in proteolytic cascades that evade innate antiviral responses.^[72]

Coronaviruses Including SARS-CoV-2

TMPRSS2 promotes SARS-CoV-2 entry into host cells by cleaving the viral spike (S) protein at the S2' site downstream of the S1/S2 polybasic cleavage site, which exposes the fusion peptide and facilitates direct fusion at the plasma membrane after receptor binding to ACE2.^[5]^[73] This pathway contrasts with the endosomal route reliant on cathepsin proteases, enabling more efficient cell-to-cell spread in TMPRSS2-expressing respiratory epithelia.^[66] The necessity of TMPRSS2 for optimal infectivity holds across variants, including Omicron, as evidenced by reduced viral replication in TMPRSS2-deficient murine airways and human cell models.^[48] Experimental validation includes antisense-mediated TMPRSS2 knockdown in Calu-3 lung cells, which blocked SARS-CoV-2 S protein activation and infection, while overexpression enhanced pseudovirus entry.^[49] Pharmacological inhibition with serine protease antagonists like camostat or nafamostat similarly impairs entry in vitro and ex vivo, confirming TMPRSS2's catalytic role via its serine protease domain.^[74]^[75] However, in primary human nasal epithelial cultures, SARS-CoV-2 replication shows partial independence from TMPRSS2, suggesting compensatory endosomal mechanisms in some contexts.^[76] Beyond SARS-CoV-2, TMPRSS2 activates spikes of other human coronaviruses, including SARS-CoV, HCoV-229E, and HCoV-HKU1, by analogous cleavage, favoring plasma membrane entry over cathepsin-dependent pathways in airway cells.^[77]^[78]^[79] For SARS-CoV, TMPRSS2 cleavage enhances infectivity while evading neutralizing antibodies, underscoring its broader contribution to coronavirus pathogenesis in the upper and lower respiratory tract.^[65]

Influenza and Other Respiratory Viruses

TMPRSS2 serves as a key host protease in the activation of influenza A viruses by cleaving the hemagglutinin (HA) glycoprotein at its monobasic cleavage site, which is essential for triggering membrane fusion between the viral envelope and host cell endosome, thereby enabling viral genome release and productive infection.^[80] This process occurs primarily in the respiratory epithelium, where TMPRSS2 is abundantly expressed, and supports multicycle replication of seasonal H1N1 and H3N2 strains as well as emerging subtypes like H7N9 in both human airway cells and animal models.^[81] ^[75] Studies in TMPRSS2-knockout mice demonstrate severely impaired H1N1 virus pathogenesis, with reduced viral titers in lungs and diminished spread, underscoring its non-redundant role in vivo for certain influenza strains.^[70] In primary human airway epithelial cells, TMPRSS2 acts as the predominant HA-activating protease for nearly all influenza A virus subtypes possessing monobasic cleavage sites, outperforming other proteases like HAT in efficiency and subcellular localization, where it processes HA intracellularly during virion assembly.^[82] ^[83] Inhibition of TMPRSS2 significantly attenuates influenza propagation in vitro and in vivo, with camostat mesylate—a serine protease inhibitor—reducing viral loads by blocking HA cleavage, though redundancy with proteases like TMPRSS11D can occur in some contexts.^[84] Beyond influenza, TMPRSS2 facilitates entry of certain paramyxoviruses, including human parainfluenza viruses (types 1 and 2) and Sendai virus, by proteolytically activating their fusion glycoproteins, promoting syncytium formation and viral spread in airway cells.^[85] This broadens TMPRSS2's utility as a therapeutic target for multiple respiratory pathogens, as evidenced by inhibitors like nafamostat suppressing parainfluenza replication alongside influenza.^[86] However, TMPRSS2 dependency varies by virus subtype and host species, with less evidence for its role in viruses like respiratory syncytial virus, where alternative furin-like proteases predominate.^[87]

Emerging Roles in Other Conditions

TMPRSS2 has been implicated in the pathogenesis of several malignancies beyond prostate cancer, with elevated expression observed in tumor tissues of bladder, kidney, liver, breast, and melanoma, potentially serving as a prognostic biomarker in these contexts.^[88] ^[89] In bladder cancer, TMPRSS2 demonstrates higher expression levels compared to normal tissues, correlating with immune infiltration patterns that may influence tumor progression.^[89] Similarly, in breast cancer, altered TMPRSS2 expression—often reduced—has been linked to overall survival and disease-free survival outcomes, suggesting a role in modulating tumor immunogenicity and therapeutic response.^[90] These findings indicate TMPRSS2's broader involvement in epithelial-derived cancers, though its precise mechanistic contributions, such as proteolytic activation of growth factors or substrates, remain under investigation across these types.^[88] Beyond oncology, TMPRSS2 exhibits a physiological role in male reproduction, localized to the apical surface of prostate epithelial cells and incorporated into prostasomes—vesicles released into seminal fluid that enhance sperm motility and function.^[91] This positioning suggests TMPRSS2 facilitates proteolytic processing events critical for fertility, potentially by activating substrates involved in semen liquefaction or pathogen defense within the reproductive tract.^[92] Studies have noted its presence in prostasomes, implying a contribution to normal reproductive physiology rather than pathology, though dysregulation could impact fertility outcomes in conditions like prostatitis.^[91] Limited evidence links TMPRSS2 variants or expression changes to infertility risks, but its androgen-regulated nature underscores a sexually dimorphic function in reproductive health.^[93]

Genetic Variations

Common Polymorphisms and Mutations

The TMPRSS2 gene contains several common single nucleotide polymorphisms (SNPs), with rs12329760 (c.589C>T, p.Val160Met) representing a prominent missense variant in the protease domain.^[94] This SNP substitutes valine with methionine at amino acid position 160, potentially altering enzymatic activity by affecting protein stability or substrate interaction.^[95] Another frequently studied variant is rs2070788, located in a regulatory region that influences TMPRSS2 expression levels.^[96] The minor allele frequency (MAF) of rs12329760 is approximately 0.25 across global populations, with elevated rates in East Asians (up to 0.38 per gnomAD data) and lower frequencies in Europeans (around 0.20).^[97] ^[98] Population-specific distributions reflect evolutionary pressures, as the T allele (encoding methionine) predominates in regions with historical exposure to respiratory pathogens.^[94] For rs2070788, allele frequencies vary similarly but have shown less consistent population stratification in large cohorts.^[99] These polymorphisms have been linked to altered TMPRSS2 function, particularly in viral entry processes. The rs12329760 T allele correlates with reduced risk of severe COVID-19, with homozygous carriers exhibiting up to 40% lower odds of hospitalization or death in multiple cohorts, likely due to impaired cleavage of the SARS-CoV-2 spike protein.^[97] ^[100] Similarly, rs2070788 genotypes have shown associations with COVID-19 susceptibility in dominant inheritance models, though effects on protease activity remain under investigation.^[99] In prostate cancer, direct germline polymorphisms in TMPRSS2 exhibit weak or inconsistent links to risk or TMPRSS2-ERG fusion status, with somatic rearrangements far more prevalent than point variants.^[101] Germline mutations in TMPRSS2 are rare and not commonly implicated in mendelian disorders, though targeted sequencing has identified low-frequency variants potentially modulating androgen-responsive expression.^[94]

Effects on Disease Outcomes

Certain single nucleotide polymorphisms (SNPs) in the TMPRSS2 gene have been associated with altered susceptibility and severity of COVID-19, primarily through modulation of viral entry efficiency via impacts on protease activity or expression levels. For example, the rs12329760 polymorphism has demonstrated an association with increased disease severity in cohorts from Ukraine, where the minor allele correlated with higher rates of hospitalization and intensive care needs.^[102] Similarly, the rs75603675 missense variant has been identified as a predictor of severe outcomes, with its presence linked to elevated risk in multivariate models incorporating comorbidities and sex, potentially due to enhanced SARS-CoV-2 spike protein priming.^[103] In contrast, the rs2070788 variant exhibits a protective effect against severe COVID-19 in some studies, reducing hospitalization odds by impairing TMPRSS2-mediated cleavage and thereby limiting viral infectivity.^[99] These associations, however, vary by population and require replication, as not all analyses confirm consistent directional effects across ethnic groups.^[104] The p.Val197Met (V197M) substitution in TMPRSS2 has been evaluated for its role in COVID-19 progression, with methionine replacement potentially reducing enzymatic efficiency and correlating with milder symptoms in affected individuals, though evidence remains preliminary and cohort-specific.^[105] Broader meta-analyses suggest that minor alleles of select TMPRSS2 SNPs, such as rs17854725, heighten vulnerability to infection and severe respiratory failure, possibly by upregulating surface protease availability for spike protein activation.^[106] In prostate cancer patients concurrently infected with SARS-CoV-2, TMPRSS2 SNPs have been implicated in exacerbated COVID-19 severity, with certain genotypes amplifying risks in those with underlying TMPRSS2-driven tumors.^[107] In prostate cancer, germline polymorphisms in TMPRSS2 influence outcomes indirectly by predisposing to TMPRSS2-ERG gene fusions, which occur in approximately 50% of cases and correlate with aggressive phenotypes, higher Gleason scores, and increased metastasis risk.^[108] For instance, the Met160Val variant has been linked to earlier-onset disease, potentially via altered androgen-responsive expression that promotes fusion events and tumor progression.^[109] Presence of TMPRSS2-ERG fusions, facilitated by such variants, is associated with biochemical recurrence and prostate cancer-specific mortality in multiple cohorts, independent of other prognostic factors like PSA levels.^[110] However, direct impacts of non-fusion-related TMPRSS2 mutations on cancer outcomes are less established, with most evidence pointing to somatic alterations rather than germline polymorphisms driving prognosis.^[111] Emerging data also explore TMPRSS2 variants in other conditions, such as influenza susceptibility, where reduced protease function from specific SNPs may attenuate viral replication and lessen pneumonia severity, though clinical correlations are inconsistent.^[100]

Therapeutic Targeting

Inhibitor Development and Mechanisms

Development of TMPRSS2 inhibitors has focused on targeting its serine protease activity, which cleaves the S2' site of viral spike proteins to facilitate membrane fusion and entry, particularly for SARS-CoV-2 and other coronaviruses.^[10] Early efforts repurposed existing synthetic serine protease inhibitors, such as camostat mesylate and nafamostat mesylate, originally approved for pancreatitis and as anticoagulants, respectively.^[112] These compounds competitively bind the enzyme's active site, forming a covalent acyl-enzyme intermediate that irreversibly inactivates TMPRSS2.^[113] The catalytic mechanism of inhibition involves nucleophilic attack by the active site serine (Ser441) on the carbonyl carbon of the inhibitor's guanidinobenzoyl group, stabilized by the oxyanion hole and the catalytic triad (His296, Asp345, Ser441).^[114] Camostat is rapidly metabolized in plasma to its active form, 3-carboxy-4-guanidinophenylglycine (GBPA), which exhibits similar binding dynamics but with transient Michaelis complex formation before covalent linkage.^[113] Nafamostat demonstrates higher potency (IC50 ~5-10 nM vs. camostat's ~50 nM against TMPRSS2), attributed to stronger electrostatic interactions with Asp345 and His296, though its shorter half-life limits systemic efficacy.^[115] Both inhibitors block TMPRSS2-mediated priming of viral spikes on host cell surfaces, reducing infectivity in lung epithelial models by over 90% at micromolar concentrations.^[116]^[117] Subsequent development leveraged virtual screening and structure-based design to identify selective TMPRSS2 inhibitors, addressing off-target effects on related proteases like matriptase. Pharmacophore models based on the TMPRSS2 catalytic pocket screened millions of compounds, yielding hits like debrisoquine and sulfonamide derivatives with IC50 values below 1 μM.^[118]^[119] A novel class, exemplified by MM3122 (developed in 2021), features a peptidomimetic scaffold that potently inhibits TMPRSS2 (IC50 84 nM) while sparing trypsin-like enzymes, blocking SARS-CoV-2 and MERS-CoV entry in human airway cells with EC50 ~100 nM.^[75] Recent advances include bispecific inhibitors like TMP1 (reported July 2025), which concurrently target TMPRSS2 and SARS-CoV-2 Mpro via non-covalent binding to the S1 pocket and covalent warhead, achieving oral bioavailability and synergistic antiviral effects in preclinical models.^[120] Peptide-derived inhibitors, such as trypsatin (identified January 2025 from human fluid libraries), exhibit broad-spectrum activity against TMPRSS2-dependent viruses, retaining efficacy in mucus-laden airways by competitively occluding the active site without covalent modification.^[121] These developments prioritize selectivity and pharmacokinetics to overcome limitations of first-generation inhibitors, with ongoing optimization for clinical translation.^[122]

Preclinical and Clinical Evidence

Preclinical studies have established that TMPRSS2 inhibitors effectively block viral entry for SARS-CoV-2 and other coronaviruses by preventing proteolytic cleavage of the spike protein in cell lines such as Calu-3 lung epithelial cells, with camostat mesylate demonstrating an IC50 of approximately 6.2 nM against TMPRSS2 activity.^[123] In hamster models of SARS-CoV-2 infection, nafamostat mesylate administration reduced viral replication in lung tissues and attenuated disease severity, providing evidence of in vivo efficacy.^[117] Novel peptidomimetic and small-molecule inhibitors, identified through virtual screening and enzymatic assays, have shown potent TMPRSS2 inhibition (IC50 values in the nanomolar range) and blocked SARS-CoV-2 infection in Vero-TMPRSS2 cells without significant off-target effects on related proteases.^[124]^[125] These findings support TMPRSS2 as a viable antiviral target, though selectivity challenges persist due to its homology with other serine proteases.^[75] In prostate cancer models, TMPRSS2 inhibition via small molecules or overexpression of its natural inhibitor HAI-2 has reduced cancer cell invasion and metastatic potential in vitro, with one study reporting significant suppression of matrigel invasion in TMPRSS2-expressing prostate cell lines.^[126] Androgen deprivation, which downregulates TMPRSS2 expression, has also shown preclinical benefits in reducing prostate tumor progression linked to TMPRSS2 activity, though direct small-molecule inhibitors remain underexplored beyond initial screens.^[127] No preclinical data indicate broad toxicity from TMPRSS2 inhibition in non-diseased tissues, as the protease's expression is largely confined to prostate epithelium and airway cells.^[10] Clinical evidence primarily derives from COVID-19 trials, where camostat mesylate was tested in multiple randomized controlled trials (RCTs). A phase II double-blind RCT in mild-to-moderate cases (n=197) found camostat safe but without significant reduction in time to symptom resolution or hospitalization risk compared to placebo.^[128] Another phase II trial in early symptomatic patients (n=120) reported no efficacy in viral clearance or clinical outcomes, though tolerability was high.^[129] A 2024 meta-analysis of RCTs for camostat and nafamostat concluded inconclusive evidence for mortality reduction, with limited data on severe disease endpoints.^[130] For nafamostat mesylate, a Bayesian RCT in hospitalized COVID-19 patients (n=100) yielded a 93% posterior probability of reduced odds for death or organ support, alongside viral load decreases in nasopharyngeal swabs by day 6.^[131] The RACONA trial (n=78) confirmed safety in moderate-to-severe cases, with trends toward improved oxygenation but no statistical significance in primary endpoints.^[132] No dedicated clinical trials have evaluated TMPRSS2 inhibitors for prostate cancer, though indirect modulation via androgen receptor antagonists, which suppress TMPRSS2 transcription, is standard in advanced disease management.^[133] Overall, while preclinical potency is clear, clinical translation for antivirals has been modest, highlighting needs for improved bioavailability and combination strategies.^[134]

References

[1]
TMPRSS2 transmembrane serine protease 2 [ (human)] - NCBI
Sep 5, 2025 · This gene encodes a protein that belongs to the serine protease family. The encoded protein contains a type II transmembrane domain, ...
[2]
TRANSMEMBRANE SERINE PROTEASE 2; TMPRSS2 - OMIM
Cloning of the TMPRSS2 gene, which encodes a novel serine protease with transmembrane, LDLRA, and SRCR domains and maps to 21q22.3.
[3]
Structure and activity of human TMPRSS2 protease implicated in ...
Jun 8, 2022 · TMPRSS2 belongs to the type 2 transmembrane serine protease (TTSP) family that comprises 19 surface-expressed trypsin-like serine proteases ...
[4]
TMPRSS2, a Serine Protease Expressed in the Prostate on the ... - NIH
TMPRSS2, an androgen responsive gene, is highly expressed in prostate epithelial cells and in human prostate cancers. Here we report new insights into the ...
[5]
SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is ...
Mar 5, 2020 · SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.Missing: peer | Show results with:peer
[6]
The Host Protease TMPRSS2 Plays a Major Role in In Vivo ...
Our data showed that TMPRSS2 is the key host protease that activates IAVs in vivo through proteolytic cleavage of their HA proteins.
[7]
The pivotal role of TMPRSS2 in coronavirus disease 2019 and ... - NIH
Jul 13, 2020 · The role of this gene fusion is crucial in the development of prostate cancer because it leads to the activation of ERG transcription factor. In ...
[8]
Structural basis of TMPRSS2 zymogen activation and recognition by ...
Aug 8, 2024 · TMPRSS2 is a type II single-pass transmembrane protein with an N-terminal cytosolic tail and an ectodomain containing a low-density lipoprotein ...
[9]
Cloning of the TMPRSS2 gene, which encodes a novel serine ...
Using selected trapped exons, we have identified a novel gene (named TMPRSS2) that encodes a multimeric protein with a serine protease domain. The TMPRSS2 ...Missing: initial discovery
[10]
The discovery and development of transmembrane serine protease ...
One important member of the TTSP subgroup is TMPRSS2, which was first discovered in 1997 by Paoloni-Giacobino et al. using exon-trapping [20]. The TMPRSS2 gene ...
[11]
https://pubmed.ncbi.nlm.nih.gov/10485450/
[12]
The TMPRSS2:ERG Rearrangement, ERG Expression, and Prostate ...
Since its discovery in 2005, the common gene fusion TMPRSS2:ERG has been extensively studied as a possible biomarker for prostate cancer progression with mixed ...
[13]
https://pubmed.ncbi.nlm.nih.gov/20926566/
[14]
SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is ...
2020 Apr 16;181(2):271-280.e8. doi: 10.1016/j.cell.2020.02.052. Epub 2020 Mar 5. Authors. Markus Hoffmann , Hannah Kleine-Weber , Simon Schroeder , Nadine ...
[15]
SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is ...
Apr 16, 2020 · Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming.
[16]
TMPRSS2-mediated SARS-CoV-2 uptake boosts innate ... - PNAS
We report that transmembrane protease serine 2 (TMPRSS2) enhances severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) internalization into endosomes.
[17]
TRANSMEMBRANE SERINE PROTEASE 2; TMPRSS2 - OMIM
The TMPRS22 and ERG genes are arranged tandemly on chromosome 21q22. The TMPRSS2/ERG fusion joins TMPRSS2 exons 1 or 2 usually to ERG exons 2, 3 or 4, which ...Missing: introns structure
[18]
ACE2 and TMPRSS2 polymorphisms in various diseases with ...
TMPRSS2 gene is expressed in many human tissues and plays a critical role in spreading the infection of the viruses including coronavirus and progression of ...<|control11|><|separator|>
[19]
https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000184012
[20]
Computational analysis of TMPRSS2 expression in normal and ...
Jul 17, 2021 · In this study, we analyzed the TMPRSS2 expression in 30 normal human tissues and compared TMPRSS2 expression levels between males and females ...
[21]
Expression Pattern of the SARS-CoV-2 Entry Genes ACE2 and ...
TMPRSS2 is highly expressed in small airway epithelium and nasal epithelium and has lower expression in masticatory mucosa. Our results provide the molecular ...
[22]
Decreased TMPRSS2 expression by SARS-CoV-2 predicts the poor ...
Jan 11, 2022 · Consistent with previous studies, we observed that TMPRSS2 was highly expressed in internal tissues (small intestine, kidney, colon, lung, liver ...
[23]
Effects and regulation of ACE2 and TMPRSS2 abundance in healthy ...
ACE2 and TMPRSS2 mRNA expression and protein levels are highest in the GI tract, kidney, and reproductive organs, while there are comparatively much lower ...
[24]
ACE2 & TMPRSS2 Expressions in Head & Neck Tissues
Aug 20, 2020 · ACE2 and TMPRSS2 were expressed in oral, pharyngeal, sinusonasal human mucosa. The following cell types expressed ACE2: basal, apical, goblet, ...
[25]
TMPRSS2: A Key Host Factor in SARS-CoV-2 Infection and ... - NIH
Jun 26, 2025 · The TMPRSS2 gene plays a critical role in SARS-CoV-2 infection by helping the virus enter human cells. It does so by priming the viral spike ...
[26]
Androgen regulation of the TMPRSS2 gene and the effect of a SNP ...
In this study, we showed that an enhancer at 13 kb upstream of the TMPRSS2 transcription start site is crucial for the androgen regulation of the TMPRSS2 gene.
[27]
The program of androgen-responsive genes in neoplastic prostate ...
This cohort includes the vast majority of genes previously shown to be androgen-regulated in prostate epithelium, such as KLK3/PSA, KLK2, NKX3A, TMPRSS2, TMEPA1 ...<|separator|>
[28]
Distinct mechanisms for TMPRSS2 expression explain organ ...
Feb 8, 2021 · Enzalutamide effectively inhibited SARS-CoV-2 infection in human prostate cells, however, such antiviral efficacy was lacking in human lung cells and organoids.
[29]
Article Targeting androgen regulation of TMPRSS2 and ACE2 as a ...
Mar 19, 2021 · As one of the most androgen-responsive gene, TMPRSS2 transcript and protein levels showed downregulation in the steroid-deprived cells compared ...
[30]
TMPRSS2 Expression and Activity Modulation by Sex-Related ...
May 30, 2022 · As TMPRSS2 is an androgen responsive gene (7, 19, 20) but it is also regulated by estrogen (18) we first searched for possible changes in ...
[31]
The Transmembrane Protease TMPRSS2 as a Therapeutic Target ...
The human TMPRSS2 gene is located on chromosome 21 (21q22.3) and comprises 14 exons and 13 introns [6,18]. Genetic analysis revealed the presence of an androgen ...
[32]
Identification of the critical residues of TMPRSS2 for entry and host ...
Nov 11, 2024 · Human TMPRSS2 is a member of type II transmembrane serine proteases, consisting of 492 amino acids with an N-terminal intracellular domain, a ...
[33]
Structural insights and inhibition mechanism of TMPRSS2 by ...
The present homology model of TMPRSS2 possesses two extracellular domains; cysteine-rich domain (residues 148–242) and serine protease domain (residues 255–489) ...Missing: architecture | Show results with:architecture
[34]
The Transmembrane Protease Serine 2 (TMPRSS2) Non ... - NIH
We found a 21-amino acid (aa) region within the scavenger receptor cysteine-rich domain (SRCR) of TMPRSS2 that binds to Spike. Our analysis revealed that ...Missing: architecture | Show results with:architecture
[35]
Molecular basis of TMPRSS2 recognition by Paeniclostridium ...
Mar 4, 2024 · The proteolytic activity of TMPRSS2 was achieved by the catalytic triad composed of S441-H296-D345 (Fig. 5a). Based on the structure of TcsH- ...
[36]
7MEQ: Crystal structure of human TMPRSS2 in complex with ...
Apr 21, 2021 · We present here a recombinant production strategy for enzymatically active TMPRSS2 and characterization of its matured proteolytic activity.
[37]
[PDF] Structure, activity and inhibition of human TMPRSS2, a protease ...
Jun 24, 2021 · The SRCR domain confers additional diversity for molecular recognition. 106. The SRCR domain is found enriched in proteins expressed at the ...
[38]
Transmembrane protease serine 2 - Proteopedia, life in 3D
This autocatalytic cleavage activates the 492-residue long TMPRSS2 zymogen. ... Structure-based drug repositioning over the human TMPRSS2 protease domain ...
[39]
TMPRSS2 - Transmembrane protease serine 2 - UniProt
Participates in proteolytic cascades of relevance for the normal physiologic function of the prostate (PubMed:25122198). Androgen-induced TMPRSS2 activates ...
[40]
Transmembrane serine protease 2 (TMPRSS2) proteolytically ... - NIH
TMPRSS2 is a trypsin-like serine protease in which the catalytic triad is formed by conserved histidine, aspartate, and serine residues (59, 60, 61).
[41]
[PDF] Structural basis of TMPRSS2 zymogen activation and recognition by ...
Feb 22, 2024 · The active site of the enzyme contains the catalytic triad H296-D345-S441, which cleaves after arginine 255 of the zymogen, at the peptide ...<|control11|><|separator|>
[42]
Transmembrane serine protease TMPRSS2 implicated in SARS ...
Oct 25, 2022 · Our results show that TMPRSS2 is activated intracellularly by autocatalysis in human kidney, airway, and lung-derived cells and that N- ...
[43]
Transmembrane serine protease 2 (TMPRSS2) proteolytically ...
TMPRSS2 is a trypsin-like serine protease in which the catalytic triad is formed by conserved histidine, aspartate, and serine residues (59, 60, 61). TMPRSS2 ...
[44]
The Androgen-Regulated Protease TMPRSS2 Activates aProteolytic ...
TMPRSS2 is an androgen-regulated cell surface serine protease expressed predominantly in prostate epithelium. TMPRSS2 is expressed highly in localized ...
[45]
Androgen-Induced TMPRSS2 Activates Matriptase and Promotes ...
In this report, we addressed the functional role of TMPRSS2 in androgen-induced prostate cancer cell invasion, tumor growth, and metastasis and identified the ...
[46]
Inhibition of TMPRSS2 by HAI-2 reduces prostate cancer cell ...
Aug 10, 2020 · TMPRSS2 is an important membrane-anchored serine protease involved in human prostate cancer progression and metastasis.<|separator|>
[47]
Structural basis of TMPRSS11D specificity and autocleavage ...
May 10, 2025 · To study the TMPRSS11D ectodomain with its native zymogen activation motif, we introduced a catalytic serine mutation, S368A, which improved ...
[48]
Essential role of TMPRSS2 in SARS-CoV-2 infection in murine airways
Oct 15, 2022 · This study shows that TMPRSS2 is critically important for SARS-CoV-2 infection of murine airways, including the Omicron variant.
[49]
TMPRSS2 and furin are both essential for proteolytic activation of ...
Jul 23, 2020 · In 2006, we first identified TMPRSS2 as a virus-activating protease ... virus entry to release the virus genome into the host cell. CoV ...Missing: discovery | Show results with:discovery
[50]
Androgen Regulation of the TMPRSS2 Gene and the Effect of a SNP ...
TMPRSS2 is predominantly expressed in the luminal cells of the prostate epithelium, where its expression is positively regulated by androgens (4–7). Despite the ...
[51]
TMPRSS2:ERG fusion by translocation or interstitial deletion is ...
Nov 15, 2006 · All five androgen-dependent xenografts showed as major transcript overexpression of two splice variants of TMPRSS2:ERG, linking TMPRSS2 exon ...
[52]
Androgen regulation of pulmonary AR, TMPRSS2 and ACE2 with ...
May 27, 2021 · TMPRSS2 is also a widely studied androgen-regulated gene in prostate tissue, contributing to prostate cancer pathogenesis by way of aberrantly ...
[53]
Targeting androgen regulation of TMPRSS2 and ACE2 as a ...
Mar 19, 2021 · TMPRSS2 is a widely studied androgen-regulated gene associated with prostate cancer (Afar et al., 2001). It contributes to prostate cancer ...
[54]
Reactivation of Androgen Receptor Regulated TMPRSS2:ERG ...
Aug 1, 2009 · These results demonstrate that expression of TMPRSS2:ERG, similarly to other AR regulated genes, is restored in CRPC and may contribute to tumor progression.
[55]
TMPRSS2-ERG Fusion Gene Expression in Prostate Tumor Cells ...
This review focuses on the clinical and biological significance of TMPRSS2-ERG fusions and their role in PC development and progression.
[56]
Prevalence of TMPRSS2-ERG fusion prostate cancer among men ...
In the current study of a PSA-screened U.S. cohort, we demonstrate that TMPRSS2-ERG fusion prostate cancer has a prevalence of 46% in prostate needle biopsies, ...
[57]
Exploring therapeutic applications of PTEN, TMPRSS2:ERG fusion ...
Mar 16, 2025 · Our findings demonstrate the importance of PTEN and TMPRSS2 : ERG fusion and Tumour Molecular Subtyping in Prostate cancer precision medicine.Missing: timeline | Show results with:timeline
[58]
TMPRSS2:ETS gene fusions in prostate cancer
The TMPRSS2:ERG gene fusion is the principle genomic alteration and a characteristic signature in approximately half of prostatic malignancies.
[59]
Role of the TMPRSS2-ERG Gene Fusion in Prostate Cancer - NIH
Together, our in vivo and in vitro studies show that the most common TMPRSS2-ERG fusion product is unable to transform benign prostatic epithelial cell lines or ...
[60]
Article An Integrated Network of Androgen Receptor, Polycomb, and ...
May 18, 2010 · Article. An Integrated Network of Androgen Receptor, Polycomb, and TMPRSS2-ERG Gene Fusions in Prostate Cancer Progression.
[61]
Etiology of prostate cancer with the TMPRSS2:ERG fusion: A ...
Dec 11, 2024 · The prevalence of TMPRSS2:ERG-positive tumors among diagnosed cases differs by race and is lower among Black men than White men. In ...3 Results · 3.5 Sex Hormones And... · 4 Discussion
[62]
The TMPRSS2:ERG Fusion and Response to Androgen Deprivation ...
Harboring the TMPRSS2:ERG fusion was associated with a statistically significant lower risk of prostate cancer mortality among men who were treated with ...<|separator|>
[63]
Urine TMPRSS2: ERG Fusion Transcript as a Biomarker for Prostate ...
A commercially available assay combining serum PSA with urinary PCA3 and TMPRSS2:ERG provides a 90% specificity and 80% sensitivity in diagnosing PCa.
[64]
Exploring therapeutic applications of PTEN, TMPRSS2:ERG fusion ...
Mar 17, 2025 · Our findings demonstrate the importance of PTEN and TMPRSS2:ERG fusion and tumour molecular subtyping in prostate cancer precision medicine.
[65]
Evidence that TMPRSS2 Activates the Severe Acute Respiratory ...
We show that TMPRSS2 might promote viral spread and pathogenesis by diminishing viral recognition by neutralizing antibodies and by activating SARS S for cell- ...
[66]
TMPRSS2 expression dictates the entry route used by SARS‐CoV‐2 ...
This study shows that SARS‐CoV‐2 infects cells through distinct, mutually exclusive entry routes (eg, pH independent versus pH dependent)
[67]
Proteolytic activation of the SARS-coronavirus spike protein
TMPRSS2 activates the spike protein at the plasma membrane. •. SARS- and MERS-coronavirus exploit the same proteases for activation. Keywords: SARS, Cathepsin L ...
[68]
TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human ...
3E). These studies show that TMPRSS2 and TMPRSS4 activate SARS-CoV-2 S and enhance membrane fusion.
[69]
TMPRSS2 Is the Major Activating Protease of Influenza A Virus in ...
This study demonstrates that the transmembrane protease TMPRSS2 is the major HA-activating protease of IAV in primary human bronchial cells and of both IAV and ...
[70]
Tmprss2 Is Essential for Influenza H1N1 Virus Pathogenesis in Mice
Dec 5, 2013 · Here, we report that the deletion of a single host protease gene, Tmprss2, in mice protects the host against viral spread in infected lungs.Missing: mechanism | Show results with:mechanism
[71]
Proteolytic Activation of Influenza Viruses by Serine Proteases ...
Here we cloned two human type II transmembrane serine proteases with known airway localization, TMPRSS2 and HAT, into mammalian expression vector.
[72]
Influenza and SARS-Coronavirus Activating Proteases TMPRSS2 ...
Our results show that TMPRSS2 and HAT are expressed by important influenza and SARS-coronavirus target cells and could thus support viral spread in the human ...<|separator|>
[73]
TMPRSS2 and furin are both essential for proteolytic activation ... - NIH
Mar 20, 2020 · We demonstrate that TMPRSS2 is essential for activation of SARS-CoV-2 S in Calu-3 human airway epithelial cells through antisense-mediated knockdown of TMPRSS2 ...
[74]
SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is ...
Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming.
[75]
A novel class of TMPRSS2 inhibitors potently block SARS-CoV-2 ...
Herein, we report on the discovery of a class of substrate-based ketobenzothiazole (kbt) inhibitors of TMPRSS2 with potent antiviral activity against SARS-CoV-2 ...
[76]
The respective roles of TMPRSS2 and cathepsins for SARS-CoV-2 ...
Nov 27, 2024 · The type II transmembrane serine protease TMPRSS2 is crucial for SARS-CoV-2 infection in lung epithelial Calu-3 cells and murine airways.
[77]
Wild-type human coronaviruses prefer cell-surface TMPRSS2 to ...
4), and the data from this study show that their infectivity was dependent on the expression of TMPRSS2. This idea supports the findings in this study ...
[78]
TMPRSS2 Activates the Human Coronavirus 229E for Cathepsin ...
Inhibition of endogenous cathepsin L or TMPRSS2 demonstrated that both proteases can activate 229E-S for entry into cells that are naturally susceptible to ...<|separator|>
[79]
Human coronavirus HKU1 recognition of the TMPRSS2 host receptor
Jul 3, 2024 · It was initially discovered in 2005 in nasopharyngeal aspirates obtained from a 71-year-old man with pneumonia in Hong Kong.<|separator|>
[80]
TMPRSS2 Is the Major Activating Protease of Influenza A Virus in ...
Cleavage of the viral surface glycoprotein hemagglutinin (HA) by host proteases is a prerequisite for membrane fusion and essential for virus infectivity.
[81]
TMPRSS2 Independency for Haemagglutinin Cleavage In Vivo ...
Jul 8, 2016 · Recent studies have revealed that the host protease TMPRSS2 plays an essential role for proteolytic activation of H1, H3, and H7 subtype strains of influenza A ...
[82]
Hemagglutinins of Avian Influenza Viruses Are Proteolytically ...
Sep 27, 2021 · Our data demonstrate that in human and murine respiratory cells, TMPRSS2 is the major activating protease of almost all IAV HA subtypes with monobasic cleavage ...
[83]
Cleavage of Influenza Virus Hemagglutinin by Airway Proteases ...
TMPRSS2 cleaves HA within the cell, while HAT cleaves HA at the cell surface and, thereby, supports cleavage of newly synthesized HA, as well as HA of incoming ...
[84]
Inhibition of Influenza A virus propagation by ... - Nature
May 6, 2020 · The redundant physiological functional host serine protease TMPRSS2 is hijacked by many subtypes influenza A virus and plays an important role ...
[85]
TMPRSS2 Is an Activating Protease for Respiratory Parainfluenza ...
Here, we show that human parainfluenza viruses and Sendai virus (SeV), like other respiratory viruses, use TMPRSS2 for their activation.Missing: besides | Show results with:besides
[86]
Efficacy of Host Cell Serine Protease Inhibitor MM3122 against ...
Feb 12, 2024 · Combined, these data show that the TMPRSS2 inhibitor MM3122 reduces virus titers and inflammation after SARS-CoV-2 infection.
[87]
Airway proteases: an emerging drug target for influenza and other ...
Apr 14, 2017 · One unique benefit of blocking TMPRSS2 and related airway proteases is that, besides influenza virus, several other respiratory viruses could be ...
[88]
TMPRSS2 Serves as a Prognostic Biomarker and Correlated With ...
Apr 25, 2022 · The results showed that TMPRSS2 was highly expressed in bladder cancer, breast cancer, kidney cancer, leukemia, liver cancer, melanoma, and ...
[89]
TMPRSS2 Correlated With Immune Infiltration Serves as ... - Frontiers
As shown in Figure 1C, TMPRSS2 displayed a higher expression level in bladder cancer, kidney cancer, liver cancer, and prostate cancer, and a lower expression ...
[90]
Multi‐omics of the expression and clinical outcomes of TMPRSS2 in ...
Dec 24, 2021 · Analysis of datasets indicated that the expression level of TMPRSS2 was considerably reduced in many tumour tissues, relative to their normal ...
[91]
TMPRSS2, a Serine Protease Expressed in the Prostate on the ...
Our data suggested that TMPRSS2, an apical surface serine protease, may have a normal role in male reproduction as a component of prostasomes.
[92]
Gene of the month: TMPRSS2 (transmembrane serine protease 2)
The other key role of TMPRSS2 is in priming the viral spike protein which facilitates viral entry essential for viral infectivity. The protease activates a ...
[93]
Coronavirus disease and male fertility: a systematic review
Aug 16, 2021 · The TMPRSS2 can be released into semen via proteasomes, which are vesicles that may help sperms to have better function [22]. The high TMPRSS2 ...
[94]
TMPRSS2 gene polymorphism common in East Asians confers ...
Nov 29, 2022 · Here, we found that rs12329760 in the TMPRSS2 gene, a missense variant common in East Asian populations, contributes to protection against SARS-CoV-2 infection.
[95]
rs12329760 Polymorphism in Transmembrane Serine Protease 2 ...
Nov 22, 2022 · V160M mutation may alter the function of TMPRSS2 gene. A role in ligand and/or protein interaction has been hypothesized for the scavenger ...
[96]
A Polymorphism in the TMPRSS2 Gene Increases the Risk of Death ...
The aim was to investigate the association between TMPRSS2 gene polymorphisms and the risk of death in hospitalized patients with COVID-19.
[97]
A common TMPRSS2 variant has a protective effect against severe ...
The first experimental structure of TMPRSS2 was released in the public domain in June 2021. Although the trypsin domain was well resolved, several unstructured ...
[98]
rs12329760 Polymorphism in Transmembrane Serine Protease 2 ...
Nov 22, 2022 · The allele frequency of TMPRSS2 rs12329760 in this study is 0.23. This value is equal to the one reported in GnomAD for East Asia (0.38) ...
[99]
The association between TMPRSS2 gene rs2070788 and ...
The results show that rs2070788 is associated with disease susceptibility in all inheritance models (P < 0.05), as well as an association between rs12329760 and ...
[100]
TMPRSS2 polymorphism (rs12329760) and the severity of the ...
Feb 16, 2023 · The rs12329760 variant is a missense mutation (C to T) at position 589 of the TMPRSS2 gene, resulting in the substitution of the methionine ...
[101]
Association of prostate cancer risk variants with TMPRSS2:ERG status
The TMPRSS2:ERG gene fusion occurs in roughly 50% of prostate cancers. Genetic risk variants may influence the development of this fusion. We sought to ...
[102]
Polymorphism of tmprss2 (rs12329760) but not ace2 (rs4240157 ...
Feb 13, 2023 · Our study indicated the presence of an association between the tmprss2 rs12329760 polymorphism and the severity of COVID-19 in the Ukrainian ...
[103]
Transmembrane protease serine 2 (TMPRSS2) rs75603675 ...
May 30, 2022 · Transmembrane protease serine 2 (TMPRSS2) rs75603675, comorbidity and sex are the primary predictors of Covid-19 severity.
[104]
Genetic variants in TMPRSS2 influence SARS-CoV-2 infection ...
Apr 14, 2025 · A common TMPRSS2 variant has a protective effect against severe COVID-19. Curr. Res. Transl. Med. 70 (2), 103333. 10.1016/j.retram ...
[105]
Evaluation of relationship between TMPRSS2 p.(Val197Met) variant ...
Jan 22, 2024 · This can lower enzyme activity and stability, which is anticipated to protect against SARS-CoV-2 infection by reducing SARS-CoV-2 activation and ...
[106]
Association of TMPRSS2 Gene Polymorphisms with COVID-19 ...
Patients who carry the minor alleles of the four studied TMPRSS2 variants were rather vulnerable to COVID-19 infection. Our findings indicated that rs17854725 A ...
[107]
Effect of SNPs in TMPRSS2 to severe COVID-19 in patients with ...
May 31, 2023 · Effect of SNPs in TMPRSS2 to severe COVID-19 in patients with prostate cancer. ... Outcomes of active cancer patients with COVID-19 ...
[108]
Association of germline genetic variants with TMPRSS2-ERG fusion ...
Apr 14, 2020 · Introduction: Oncogenic activation of ERG resulting from TMPRSS2-ERG gene fusion is a key molecular genetic alteration in prostate cancer (CaP).
[109]
Met160Val TMPRSS2 gene polymorphism and early onset prostate ...
May 20, 2009 · Background: The TMPRSS2-ERG gene fusion has been found in over 50% of prostate tumors and its role is being characterized in various clinical ...
[110]
results from a population-based study of prostate cancer - PMC
The presence of the TMPRSS2-ERG fusion gene in prostate tumors has recently been associated with an aggressive phenotype, as well as recurrence and death ...
[111]
Association of TMPRSS2-ERG gene fusion with clinical ...
Aug 11, 2008 · The presence of the TMPRSS2-ERG fusion gene in prostate tumors has recently been associated with an aggressive phenotype, as well as recurrence and death from ...Missing: timeline | Show results with:timeline
[112]
Discovery of TMPRSS2 Inhibitors from Virtual Screening as a ...
We developed an efficient pharmacophore-based approach and applied a large-scale in silico database screening for small-molecule inhibitors against TMPRSS2.
[113]
Molecular mechanism of inhibiting the SARS-CoV-2 cell entry ...
Through Markov modeling, we describe the binding process of both drugs and a metabolic product of camostat (GBPA) to TMPRSS2, reaching a Michaelis complex (MC) ...
[114]
Structural insights and inhibition mechanism of TMPRSS2 by ...
May 26, 2021 · We have used a molecular dynamics (MD) simulated homology model of TMPRSS2 to study the inhibition mechanism of experimentally known inhibitors Camostat ...
[115]
Structure-based discovery of dual pathway inhibitors for SARS-CoV ...
Nov 21, 2023 · Host proteases, TMPRSS2 and CTSL/CTSB cleave the SARS-CoV-2 spike to play a crucial role in the two alternative pathways of viral entry and are ...
[116]
Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2 ...
The clinically-proven protease inhibitor Camostat mesylate inhibits SARS-CoV-2 infection by blocking the virus-activating host cell protease TMPRSS2. However, ...<|separator|>
[117]
The TMPRSS2 Inhibitor Nafamostat Reduces SARS-CoV-2 ...
Aug 3, 2021 · Both camostat and nafamostat were previously shown to directly inhibit the enzymatic activity of TMPRSS2 and related serine proteases in ...
[118]
TMPRSS2 Inhibitor Discovery Facilitated through an In Silico ... - NIH
Pentamidine and propamidine obstruct access to the catalytic triad (residues shown in lime green), whereas the fragment debrisoquine only partially reaches ...
[119]
Discovery of TMPRSS2 inhibitors from virtual screening - PMC - NIH
Dec 29, 2020 · We developed an efficient pharmacophore-based approach and applied a large-scale in silico database screening for small molecule inhibitors against TMPRSS2.
[120]
An orally available Mpro/TMPRSS2 bispecific inhibitor with potent ...
Jul 16, 2025 · Design and cloning of TMPRSS2 and its mutation constructs. The gene coding human TMPRSS2 (GenBank: KJ897688.1) was synthesized by the GENERAL ...
[121]
Trypstatin as a Novel TMPRSS2 Inhibitor with Broad‐Spectrum ...
May 14, 2025 · Respiratory viruses, such as SARS-CoV-2 and influenza, exploit host proteases like TMPRSS2 for entry, making TMPRSS2 a prime antiviral ...
[122]
Exploring TMPRSS2 Drug Target to Combat Influenza and ...
TMPRSS2 in respiratory epithelial cells cleaves the viral S protein, allowing SARS-CoV-2 to enter the host cell by membrane fusion. TMPRSS2 competes against ...
[123]
An Enzymatic TMPRSS2 Assay for Assessment of Clinical ... - NIH
... camostat (IC50 = 6.2 nM) for TMPRSS2 inhibition. There are eight registered clinical trials studying camostat, of which only one is focused on coagulopathy.
[124]
Peptidomimetic inhibitors of TMPRSS2 block SARS-CoV-2 infection ...
Jul 8, 2022 · The most potent inhibitors against matriptase and TMPRSS2 also efficiently prevented cell-mediated proteolysis of the fluorogenic substrate ...
[125]
Discovery of TMPRSS2 Inhibitors from Virtual Screening as a ...
Apr 2, 2021 · We developed an efficient pharmacophore-based approach and applied a large-scale in silico database screening for small-molecule inhibitors against TMPRSS2.
[126]
Design, synthesis and biological evaluation of novel TMPRSS2 ...
Dec 15, 2024 · In 2020, in a clinical case with lung and prostate cancers, Ardizzoni et al. discovered the dual TMPRSS2-ERG fusion for the first time.10 In ...Missing: initial | Show results with:initial
[127]
TMPRSS2 and COVID-19: Serendipity or Opportunity for Intervention?
Jun 1, 2020 · TMPRSS2, A Key Regulator in Prostate Cancer. TMPRSS2 was first identified in prostate cancer shortly after the gene had been originally cloned.
[128]
A Double-Blind, Randomized, Placebo-Controlled, Phase II Clinical ...
Dec 14, 2022 · Camostat mesylate was safe in the treatment of COVID-19. Although this study did not show clinical benefit in patients with mild to moderate ...
[129]
Efficacy and safety of camostat mesylate in early COVID-19 disease ...
Jul 5, 2022 · We conducted a phase II randomized controlled trial in symptomatic (maximum 5 days) and asymptomatic patients with confirmed COVID-19 infection.<|separator|>
[130]
TMPRSS2 inhibitors for the treatment of COVID-19 in adults - PubMed
The RCT evidence is inconclusive to determine whether there is a mortality reduction and safety with either nafamostat or camostat for the treatment of adults ...Missing: preclinical | Show results with:preclinical
[131]
A Randomized Trial of Nafamostat for Covid-19 - NEJM Evidence
Oct 18, 2023 · Among hospitalized patients with Covid-19, there was a 93% posterior probability that nafamostat reduced the odds of death or organ support.
[132]
RAndomized Clinical Trial Of NAfamostat Mesylate, A Potent ...
Oct 19, 2023 · The RACONA study showed a good safety profile of nafamostat, suggesting that it could be usefully used in COVID-19 hospitalized patients.
[133]
Androgen-deprivation therapies for prostate cancer and risk of ...
May 6, 2020 · Intriguingly, TMPRSS2 is an androgen-regulated gene that is up-regulated in prostate cancer where it supports tumor progression and is involved ...
[134]
TMPRSS2 inhibitors for the treatment of COVID-19 in adults: a ...
The RCT evidence is inconclusive to determine whether there is a mortality reduction and safety with either nafamostat or camostat for the treatment of adults ...