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STAT1

STAT1, or Signal Transducer and Activator of Transcription 1, is a transcription factor encoded by the STAT1 gene located on chromosome 2q32.2 in humans.^[1] As a key member of the STAT protein family, it mediates cellular responses to cytokines and growth factors, such as interferons (IFNs), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and interleukin-6 (IL-6), by facilitating signal transduction from the cell membrane to the nucleus.^[1] Upon activation through phosphorylation, primarily at tyrosine 701 (Y701) and serine 727 (S727) residues, STAT1 forms homodimers or heterodimers (e.g., with STAT2 in the ISGF3 complex) that translocate to the nucleus, bind to specific DNA sequences, and regulate the transcription of target genes essential for immune defense, cell viability, and antipathogen responses.^[2] Expressed ubiquitously but at higher levels in immune tissues like lymph nodes and the appendix, STAT1 is indispensable for innate and adaptive immunity, particularly in combating viral, mycobacterial, and fungal infections.^[1] Structurally, STAT1 comprises six conserved domains: an N-terminal domain (ND) for dimerization stability, a coiled-coil domain (CC) for protein interactions, a DNA-binding domain (DBD), a linker domain (LK), an Src homology 2 domain (SH2) for phosphotyrosine recognition, and a C-terminal transactivation domain (TAD) for transcriptional activation.^[2] It exists in two primary isoforms generated by alternative splicing: the longer STAT1α (91 kDa, 750 amino acids) with a full TAD, and the shorter STAT1β (84 kDa, 712 amino acids) lacking the terminal 38 amino acids of the TAD, which influences their distinct regulatory potentials.^[2] Activation occurs via the Janus kinase (JAK)-STAT pathway, where interferons bind to cell surface receptors, recruiting JAK1, JAK2, or TYK2 kinases that phosphorylate STAT1, enabling its nuclear import and binding to gamma-activated sequences (GAS) or interferon-stimulated response elements (ISREs).^[2] This process drives the expression of interferon-stimulated genes (ISGs), such as those encoding antiviral proteins like Mx1, Viperin, and IFITM family members, which inhibit viral entry, replication, and assembly.^[2] In the immune system, STAT1 maintains balance by promoting type I (IFN-α/β) and type II (IFN-γ) signaling for robust antiviral and antimycobacterial defenses while suppressing the IL-17 pathway to control Th17-mediated inflammation and antifungal responses against pathogens like Candida.^[3] It supports immunoglobulin class-switch recombination by upregulating T-bet in B cells, enhancing IgG production, and coordinates macrophage responses, including the synthesis of 25-hydroxycholesterol, which bolsters IFN antiviral activity.^[2] Dysregulation of STAT1 underlies several immunodeficiencies: gain-of-function mutations (e.g., autosomal dominant) hyperactivate STAT1, impairing IL-17 signaling and causing chronic mucocutaneous candidiasis (immunodeficiency 31C); whereas loss-of-function mutations lead to autosomal recessive forms (immunodeficiency 31A for IFN-γ defects, 31B for combined IFN-α/β and IFN-γ defects), resulting in severe susceptibility to mycobacteria, viruses, and other infections.^[4] These conditions highlight STAT1's non-redundant role in host protection, with deficiencies often proving lethal without intervention.^[2]

Gene and Expression

Genomic Location and Organization

The STAT1 gene is situated on the q arm of human chromosome 2 at cytogenetic band 2q32.2, spanning coordinates chr2:190,908,460-191,020,960 in the GRCh38.p14 assembly on the reverse strand.^[5] This locus covers approximately 113 kb and lies in proximity to the neighboring STAT4 gene, forming part of a conserved cluster of signal transducer and activator of transcription family members on chromosome 2.^[6] The genomic organization includes 25 exons, which together encode the primary transcripts of the gene, with introns varying in size but contributing to the overall compact structure.^[5] The promoter region of STAT1, located upstream of the first exon, features key regulatory elements such as gamma-interferon activation sites (GAS), which confer responsiveness to interferon-gamma (IFN-γ) signaling and enable autoregulatory feedback loops.^[7] These elements, along with additional enhancers identified through genomic annotation, facilitate inducible transcription in response to cytokines, while basal promoter activity supports constitutive expression. The gene's exon-intron boundaries are precisely defined, with the coding sequence distributed across most exons to allow for post-transcriptional modifications. Evolutionarily, the STAT1 gene exhibits strong conservation among mammals, reflecting its essential role in innate immunity. Sequence homology in the coding region reaches over 95% identity between humans and rodents like mice, with even higher conservation (near 100%) in critical functional motifs such as the DNA-binding domain and SH2 domain, as evidenced by comparative genomics across vertebrate lineages.^[8] This preservation underscores the gene's ancient origin and minimal divergence since the mammalian radiation, with orthologs identified in over 270 species. Transcriptional regulation of STAT1 maintains low to moderate basal levels across tissues, with notably higher expression in immune cells such as T lymphocytes, B cells, and macrophages, where it poises the pathway for swift activation.^[9] This baseline expression, driven by housekeeping promoters and immune-specific enhancers, ensures readiness for interferon-mediated responses without excessive activity in non-immune contexts.

Isoforms and Alternative Splicing

The STAT1 gene undergoes alternative splicing to generate multiple protein isoforms, primarily STAT1α and STAT1β, which differ in their C-terminal regions and thus exhibit distinct regulatory functions in signal transduction. STAT1α represents the full-length isoform, comprising 750 amino acids, and includes a C-terminal transactivation domain (TAD) essential for recruiting co-activators to promote gene expression. In contrast, STAT1β is a shorter variant of 712 amino acids, truncated by the absence of the 38-amino-acid TAD segment. This structural difference arises from alternative processing of the primary transcript, where the STAT1β mRNA utilizes a polyadenylation site after exon 23, excluding exons 24 and 25. The STAT1 gene consists of 25 exons in total, and this mechanism ensures the production of both isoforms from the same genomic locus.^[1]^[10] Expression patterns of the isoforms vary across tissues and cellular contexts, reflecting their roles in baseline cellular homeostasis and stress responses. STAT1α is ubiquitously expressed in human tissues, with particularly high levels observed in lymphoid organs such as lymph nodes and spleen, where it supports constitutive signaling readiness. STAT1β, while also broadly present, shows more restricted and inducible expression, often elevated in immune cells like macrophages and T cells during interferon-driven inflammatory conditions. This differential expression is regulated by tissue-specific splicing factors and cytokine stimulation, allowing fine-tuned adaptation to environmental cues.^[11] The isoform-specific structural variations lead to distinct functional implications in transcriptional regulation. STAT1α's intact TAD enables robust activation of interferon-stimulated genes (ISGs) by facilitating interactions with the transcriptional machinery, while also permitting repressive activities through DNA binding without co-activator recruitment. STAT1β, deprived of the TAD, exhibits a bias toward transcriptional repression and prolonged DNA binding upon phosphorylation, yet it retains the ability to dimerize with STAT1α and contribute to antiviral and antiproliferative responses, albeit less efficiently than the full-length form. These differences result in unique gene expression profiles; for instance, STAT1α induces a broader set of IFN-γ-responsive genes compared to STAT1β, which preferentially modulates a subset involved in immune modulation. Such isoform interplay ensures balanced JAK-STAT signaling, preventing excessive activation while maintaining protective immunity.^[12]^[13]

Protein Structure

Domain Architecture

The STAT1 protein exhibits a modular domain architecture typical of the STAT family, consisting of several conserved structural elements that facilitate its roles in signal transduction and transcriptional regulation. The full-length STAT1α isoform comprises approximately 750 amino acids, while the shorter STAT1β isoform lacks the C-terminal transactivation domain. These domains are arranged linearly from the N- to C-terminus: an N-terminal domain (NTD), a coiled-coil domain (CCD), a DNA-binding domain (DBD), a linker domain, an SH2 domain, and a transactivation domain (TAD) present only in STAT1α.81443-9)^[14] The N-terminal domain (NTD) spans the first approximately 130 amino acids (residues 1–130) and adopts a helical structure that promotes oligomerization of STAT1 molecules, enabling cooperative DNA binding and tetramer formation. This domain also contributes to nuclear import and export, facilitating the shuttling of STAT1 between cytoplasmic and nuclear compartments in response to signaling cues.^[15] The coiled-coil domain (CCD) follows, encompassing roughly 150–180 amino acids (approximately residues 131–317), and forms a bundle of alpha-helices that mediates protein-protein interactions with regulatory factors and stabilizes the overall protein fold. This domain plays a key role in maintaining the structural integrity of STAT1 dimers and higher-order assemblies.^[16]01120-2) The DNA-binding domain (DBD) consists of about 150 amino acids (residues 316–488) and features an immunoglobulin-like β-barrel fold that specifically recognizes gamma-activated site (GAS) elements in target gene promoters, characterized by the consensus motif TTCCNGGAA. This domain enables sequence-specific binding essential for transcriptional activation.81443-9) Connecting the DBD and SH2 domain is the linker domain (approximately residues 489–549), a flexible region of around 60 amino acids that modulates the sensitivity of STAT1 to phosphorylation by influencing the accessibility of the tyrosine residue in the adjacent SH2 domain. This linker is crucial for fine-tuning the responsiveness of STAT1 to upstream kinase activity.^[17]^[18] The SH2 domain, spanning approximately 100 amino acids (residues 550–650), binds phosphotyrosine residues on partner STAT1 molecules or receptors, driving dimerization and stabilizing the active conformation. This interaction is pivotal for the parallel dimer formation observed in phosphorylated STAT1.81443-9)^[19] Exclusive to the STAT1α isoform, the transactivation domain (TAD) at the C-terminus (residues 713–750, about 38 amino acids) is rich in glutamine and arginine residues, recruiting co-activators such as CBP/p300 to enhance transcriptional initiation at target genes. In contrast, STAT1β terminates earlier at residue 712, lacking this domain and thus exhibiting reduced transactivation potential.^[20]

Conformational Dynamics

In its inactive state, STAT1 predominantly adopts an antiparallel dimeric conformation in the cytoplasm, characterized by a closed structural arrangement that maintains latency. The N-terminal domain (NTD) engages in inhibitory interactions with the coiled-coil domain (CCD), effectively masking the nuclear localization signal (NLS) located within the DNA-binding domain (DBD) and preventing premature nuclear translocation.^[21]^[22] This auto-inhibitory interface, involving key residues such as glutamic acid 169 (E169) in the CCD, stabilizes the closed form and contributes to the regulation of DNA dissociation and signaling termination.^[21] Activation initiates a dynamic conformational opening triggered by tyrosine phosphorylation at residue 701 (Y701), located in the C-terminal tail following the SH2 domain. This phosphorylation event disrupts the NTD-CCD interaction, exposing the bipartite NLS in the DBD and enabling rapid nuclear import mediated by the importin-α/β heterodimer, where importin-α5 directly binds the phosphorylated STAT1 dimer.^[23]^[24] The resultant open conformation not only facilitates NLS recognition but also repositions the DBD for subsequent DNA interactions, marking a critical transition from cytoplasmic sequestration to nuclear functionality.^[23] Dimerization of activated STAT1 occurs through parallel homodimeric interfaces, stabilized by reciprocal phosphotyrosine-SH2 domain interactions where the SH2 domain of one monomer binds the pY701 motif of its partner, involving specific contacts at residues like Ile634 and Lys644 in the SH2 pocket.^[22] In contrast, unphosphorylated STAT1 favors antiparallel dimerization via extended NTD interfaces, while certain heterodimers, such as STAT1-STAT2, can adopt antiparallel orientations dependent on context-specific signaling cues.^[22]^[25] These dimerization modes underscore the versatility of STAT1's structural dynamics in response to stimuli. Deactivation restores the inactive conformation through dephosphorylation at Y701, primarily catalyzed by protein tyrosine phosphatases such as SHP-1, which associates with STAT1 via its SH2 domains to attenuate signaling.^[26] This process leads to dimer dissociation into unphosphorylated monomers or antiparallel dimers, which are then exported from the nucleus via the CRM1 (exportin-1) receptor recognizing a leucine-rich nuclear export signal in the CCD, thereby recycling STAT1 to the cytoplasm for subsequent rounds of activation.^[27]^[28]

Activation and Signaling

Mechanism of Activation

The activation of STAT1 begins with ligand binding to specific cytokine receptors, such as those for interferons (IFNs). For instance, binding of IFN-γ to its heterodimeric receptor (IFNGR1/IFNGR2) induces receptor dimerization, recruiting and activating associated Janus kinases (JAKs). This leads to JAK autophosphorylation and subsequent phosphorylation of tyrosine residues on the receptor cytoplasmic tails, creating docking sites for downstream effectors.^[29]^[30] STAT1 is then recruited to the activated receptor complex through its Src homology 2 (SH2) domain, which specifically binds to phosphotyrosine motifs on the receptor or JAKs. This interaction positions the critical tyrosine residue Y701, located between the SH2 domain and the C-terminal transactivation domain, for phosphorylation by the receptor-associated JAKs. The SH2-phosphotyrosine interaction ensures specificity and efficient kinase access, enabling rapid transfer of the phosphate group to Y701.^[31]^[32] Kinase specificity varies by ligand: IFN-γ signaling primarily involves JAK1 and JAK2 for STAT1 Y701 phosphorylation, while IFN-α engages TYK2 and JAK1. These combinations reflect the distinct receptor compositions—IFNGR associates with JAK1/JAK2, whereas the IFNAR1/IFNAR2 complex pairs TYK2 with JAK1—ensuring tailored activation responses.^[29]^[33] In addition to phosphorylated STAT1 (p-STAT1), unphosphorylated STAT1 (U-STAT1) exhibits basal nuclear localization and activity through a non-classical import mechanism independent of typical import receptors, involving direct interactions with nucleoporins. This contrasts with the classical p-STAT1 pathway, allowing U-STAT1 to maintain low-level nuclear presence without cytokine stimulation.^[34]^[23] The process displays distinct temporal dynamics, with Y701 phosphorylation occurring rapidly within 15-30 minutes of ligand exposure, followed by transient nuclear accumulation of p-STAT1 dimers that peaks shortly thereafter and declines due to dephosphorylation. Post-phosphorylation, STAT1 undergoes a conformational shift that promotes dimerization via reciprocal SH2-pY701 interactions.^[35]^[36]

Role in JAK-STAT Pathway

STAT1 serves as a central transducer in the canonical JAK-STAT signaling pathway, particularly in response to interferon (IFN) ligands. Upon binding of type I IFNs (IFN-α/β) to their heterodimeric receptors, Janus kinases (JAK1 and TYK2) are activated, leading to tyrosine phosphorylation of STAT1 at Tyr701, which enables its dimerization with STAT2 and association with IRF9 to form the ISGF3 complex. This complex translocates to the nucleus and binds to interferon-stimulated response elements (ISREs), driving the transcription of genes involved in antiviral and immunomodulatory responses. In contrast, type II IFN (IFN-γ) signaling involves homodimerization of phosphorylated STAT1 (γ-activated factor, GAF), which binds to gamma-activated sequences (GAS) to regulate distinct target genes, highlighting STAT1's versatility in mediating IFN-specific outcomes within the pathway.^[30]^[37]^[38] STAT1 activity is modulated through cross-talk with other signaling cascades, such as the MAPK/ERK and PI3K/AKT pathways, which influence its phosphorylation and transcriptional efficacy. For instance, serine phosphorylation of STAT1 at Ser727 by MAPK or PI3K-activated kinases enhances its maximal transcriptional activation in response to IFN-γ, integrating growth factor signals with cytokine responses. This interplay allows STAT1 to fine-tune cellular decisions, such as proliferation versus differentiation, by converging inputs from multiple receptors.^[30]^[39]^[40] Negative feedback mechanisms tightly regulate STAT1 to prevent excessive signaling, primarily through suppressors of cytokine signaling (SOCS) and protein inhibitors of activated STAT (PIAS) proteins. SOCS1, induced by STAT1 activation, binds to JAKs to inhibit their kinase activity and promote STAT1 dephosphorylation, forming a classic feedback loop in IFN-γ responses. Similarly, PIAS1 facilitates SUMOylation of STAT1, repressing its DNA-binding and transcriptional functions, particularly in type I IFN signaling. These regulators ensure transient and controlled STAT1 activation.^[41]^[42]^[43] Beyond canonical nuclear functions, STAT1 exhibits non-canonical roles, including localization to mitochondria where it influences reactive oxygen species (ROS) production and apoptosis. Mitochondrial STAT1, independent of tyrosine phosphorylation, interacts with the electron transport chain to modulate oxidative stress and promote caspase-dependent cell death in response to IFN signals. This extranuclear activity expands STAT1's regulatory scope in cellular homeostasis.^[44]^[45]^[46] The JAK-STAT pathway, including STAT1, is highly conserved across eukaryotes, from insects to mammals, underscoring its fundamental role in innate immunity and development. In vertebrates, expansions in STAT family members and receptor diversity, particularly in humans, have enabled specialized adaptations, such as enhanced IFN responsiveness through duplicated IFN genes and refined negative regulators.^[30]^[47]^[48]

Biological Functions

Interferon-Mediated Responses

STAT1 was first identified in 1992 as a key component of the interferon-stimulated gene factor 3 (ISGF3) complex, formed in response to type I interferons (IFNs), where it associates with STAT2 and IRF9 to drive transcriptional activation of antiviral genes. This discovery highlighted STAT1's central role in establishing an antiviral state within cells by inducing hundreds of interferon-stimulated genes (ISGs). In type I IFN signaling (IFN-α and IFN-β), ligand binding to the IFNAR receptor leads to JAK1 and TYK2-mediated phosphorylation of STAT1 at tyrosine 701, enabling its heterodimerization with phosphorylated STAT2. The STAT1-STAT2 heterodimer then recruits IRF9 to form the ISGF3 trimer, which translocates to the nucleus and binds interferon-stimulated response elements (ISREs) in ISG promoters, such as those for Mx1 (which inhibits viral nucleocapsid assembly) and OAS (which activates RNase L to degrade viral RNA). This process rapidly establishes a broad antiviral state, restricting replication of viruses like influenza and vesicular stomatitis virus.^[29]^[49] For type II IFN (IFN-γ), signaling through the IFNGR receptor involves JAK1 and JAK2 phosphorylating STAT1, promoting its homodimerization (known as gamma-activated factor, GAF). These STAT1 homodimers bind gamma-activated sites (GAS) in the promoters of target genes, upregulating expression of MHC class I and II molecules to enhance antigen presentation and inducible nitric oxide synthase (iNOS) to produce nitric oxide, which activates macrophages for bactericidal and tumoricidal activity. This pathway is crucial for Th1-mediated immune responses and control of intracellular pathogens like Mycobacterium tuberculosis.^[29]^[50]^[51] Type III IFNs (IFN-λ), which primarily act on epithelial cells via IFNLR1/IL10RB receptors, similarly activate STAT1 through JAK1 and TYK2, forming ISGF3-like complexes that bind ISREs to induce ISGs and provide localized antiviral defense at mucosal barriers. This STAT1-dependent signaling restricts viruses such as norovirus and rotavirus in intestinal epithelia, complementing type I IFN effects while minimizing systemic inflammation due to restricted receptor expression. Overall, STAT1 integrates these IFN pathways within the JAK-STAT framework to orchestrate rapid, cell-type-specific immunomodulatory responses.^[2]

Broader Cellular Roles

STAT1 participates in growth factor signaling beyond interferon pathways, notably in the interleukin-6 (IL-6) response through the gp130 receptor. In this context, IL-6 induces the formation of STAT1-STAT3 heterodimers that translocate to the nucleus and bind to gamma-activated sites (GAS) elements, driving the expression of acute phase response genes such as C-reactive protein and serum amyloid A in hepatocytes. This heterodimerization is mediated by specific tyrosine motifs in the gp130 cytoplasmic domain, which differentially activate STAT1 and STAT3 compared to homodimer formation in interferon signaling.^[52] In antitumor mechanisms, STAT1 exerts p53-independent effects on apoptosis and growth suppression, particularly in fibroblasts. For instance, in response to oxidized cholesterol derivatives like 7-ketocholesterol, STAT1 upregulates p21^WAF1/CIP1 expression in a p53-independent manner, leading to cell cycle arrest and enhanced apoptosis in mouse embryonic fibroblasts. This pathway relies on STAT1's transcriptional activity to induce p21, which inhibits cyclin-dependent kinases, thereby suppressing fibroblast proliferation and contributing to tumor-suppressive outcomes in the tumor microenvironment.^[53]^[54] STAT1 influences metabolic regulation, particularly insulin sensitivity in adipose tissue, through feedback involving SOCS3. In adipocytes, interferon-γ (IFN-γ) activates STAT1, which promotes SOCS3 expression as a negative regulator of both cytokine and insulin signaling; elevated SOCS3 inhibits insulin receptor substrate-1 (IRS-1) phosphorylation, reducing Akt activation and glucose uptake, thus contributing to insulin resistance in obesity. This STAT1-SOCS3 axis highlights STAT1's role in linking inflammation to metabolic dysfunction, where adipocyte-specific STAT1 activity modulates local insulin responsiveness without fully driving systemic effects.^[55]^[56] Regarding developmental roles, STAT1 knockout studies in mice reveal no embryonic lethality or overt vascular defects, indicating that STAT1 is dispensable for basic embryogenesis and vascular formation. However, these mice exhibit subtle impairments in vascular remodeling and endothelial function, as STAT1 is required for optimal endothelial cell migration and response to growth factors like platelet-derived growth factor, influencing postnatal vascular integrity. Conditional knockout approaches further demonstrate STAT1's involvement in modulating vascular inflammation and smooth muscle cell proliferation during development and injury repair.^[57]^[58] In epigenetic modulation, STAT1 facilitates gene repression by recruiting histone deacetylases (HDACs) to target promoters. STAT1 interacts with corepressor complexes containing HDAC1 and HDAC2, promoting histone deacetylation and chromatin condensation to silence transcription, as seen in contexts where STAT1 acts as a repressor independent of its activator role in interferon responses. This recruitment, often via intermediary proteins like PIAS1, enables STAT1 to fine-tune gene expression by maintaining repressive chromatin states at specific loci.^[59]^[25]

Clinical Significance

Loss-of-Function Mutations

Loss-of-function (LOF) mutations in STAT1 result in impaired signaling through the JAK-STAT pathway, leading to primary immunodeficiencies characterized by increased susceptibility to infections due to defective interferon responses. These mutations are rare, with an estimated prevalence of approximately 1 in 1,000,000 individuals, and have been documented in fewer than 100 cases worldwide across multiple cohorts. They are broadly classified into autosomal recessive (AR) complete deficiency, which abolishes STAT1 expression and function, and autosomal dominant (AD) partial deficiency, which exerts dominant-negative effects on wild-type STAT1. AR complete STAT1 deficiency, first described in 2003, arises from biallelic null mutations such as nonsense or frameshift variants that prevent STAT1 protein production. For instance, nonsense mutations like p.Q9* in the N-terminal domain (NTD) or frameshift mutations like c.88delA (p.Ser30Argfs*9) in the NTD truncate the protein early, eliminating responses to type I, II, and III interferons. This complete loss leads to profound vulnerability to intracellular pathogens, including severe viral infections (e.g., disseminated herpesviruses such as HSV-1, VZV, CMV, and HHV-6), pyogenic bacterial infections (e.g., Staphylococcus aureus), and mycobacterial diseases. A hallmark phenotype is disseminated BCG disease following vaccination, observed in nearly all affected individuals who receive the BCG strain, often progressing to osteomyelitis or lymphadenopathy. Patients typically present in infancy with life-threatening infections, and mortality is high, with over 60% succumbing before adulthood despite antimicrobial therapy. Hematopoietic stem cell transplantation (HSCT) offers curative potential but carries significant risks, with survival rates around 64% in reported series.^[60] In contrast, AD LOF mutations cause partial STAT1 impairment through dominant-negative mechanisms, where mutant proteins interfere with wild-type STAT1 dimerization or stability, reducing but not abolishing interferon signaling. These heterozygous variants, often missense in the SH2 domain such as K637E or nonsense mutations like those affecting the NTD, result in milder phenotypes primarily involving mycobacterial susceptibility, such as environmental mycobacteria or BCG-related disease, alongside selective viral vulnerabilities like herpesvirus infections. Unlike AR forms, AD deficiency may not manifest until later childhood and can include progressive combined immunodeficiency with declining T- and B-cell function, though infections are less uniformly severe. Diagnosis of STAT1 LOF relies on genetic sequencing to identify causative variants, complemented by functional assays such as flow cytometry to measure phosphorylated STAT1 (p-STAT1) levels in peripheral blood mononuclear cells following ex vivo stimulation with IFN-α or IFN-γ. In AR complete deficiency, p-STAT1 is absent, while AD forms show markedly reduced phosphorylation. Conventional treatments like antimycobacterial or antiviral agents provide partial control, but IFN-γ therapy is ineffective due to the upstream blockade in STAT1-dependent signaling. HSCT remains the definitive treatment for both AR and AD forms, though outcomes vary with early intervention.

Gain-of-Function Mutations

Gain-of-function (GOF) mutations in STAT1 are heterozygous, autosomal dominant variants that result in hypermorphic activity, leading to enhanced STAT1 phosphorylation and resistance to dephosphorylation upon cytokine stimulation.^[61] These mutations were first reported in 2011 in patients with autosomal dominant chronic mucocutaneous candidiasis (CMC), where they impair IL-17-mediated immunity while exaggerating interferon (IFN) responses.^[62] Common examples include R274Q in the DNA-binding domain (DBD), which stabilizes STAT1-DNA interactions, and T385M in the DNA-binding domain (DBD), which disrupts intramolecular inhibitory contacts to promote prolonged activation.^[63] Over 125 distinct GOF alleles have been identified, often clustered in the CCD, DBD, and DNA-binding interface, affecting more than 660 patients worldwide as of 2024.^[64] Clinically, STAT1 GOF mutations manifest as a multisystem disorder primarily featuring CMC due to selective vulnerability to Candida albicans and other fungi, alongside broader infectious susceptibility including bacterial and viral pathogens.^[65] Autoimmune phenomena are prominent, encompassing thyroiditis, lupus-like syndromes, interstitial lung disease, and enteropathy, driven by dysregulated IFN signaling that skews immune homeostasis.^[66] Vascular complications, such as cerebral aneurysms and aortic dilation, occur at higher rates than in the general population, potentially linked to chronic inflammation.^[67] A key immunological defect is impaired Th17 cell differentiation and function, resulting from competitive inhibition of STAT3 by hyperactive STAT1, which reduces IL-17 and IL-22 production essential for antifungal defense.^[62] The condition is rare, representing the most common monogenic cause of inherited CMC, with an estimated prevalence below 1 in 100,000, though underdiagnosis likely occurs in isolated CMC cases.^[66] At the molecular level, these mutations enhance STAT1 dimer stability and nuclear retention, leading to hypersensitivity to type I and II IFNs and ectopic expression of IFN-stimulated genes (ISGs) even at baseline.^[68] This results in upregulated transcription of genes like AIRE in non-thymic cells, contributing to autoimmunity through aberrant self-antigen presentation and loss of tolerance.^[69] Management is challenging, with antifungal prophylaxis for CMC and immunosuppression for autoimmunity; JAK inhibitors such as ruxolitinib have shown promise in reducing STAT1 hyperactivation and improving Th17 responses, but risks of disseminated infections limit their use.^[70] Hematopoietic stem cell transplantation remains curative but carries high morbidity due to infection susceptibility; recent reports indicate improved overall survival rates of about 72% with optimized protocols as of 2025.^[71] Animal models, including knock-in mice harboring human-equivalent GOF mutations like T385M, recapitulate the phenotype with exaggerated IFN-γ responses, heightened ISG expression, and spontaneous autoimmunity, underscoring the role of unchecked STAT1 in immune dysregulation.^[72] These models also reveal sex-biased severity, with females showing more pronounced Th1 skewing and T-follicular helper cell expansion.^[73]

Molecular Interactions

Protein-Protein Interactions

STAT1 engages in direct physical interactions with components of the interferon receptor complexes, primarily through its Src homology 2 (SH2) domain, which docks onto phosphotyrosine residues on the cytoplasmic tails of IFNGR1 (for IFN-γ signaling) and IFNAR subunits (for type I IFN signaling).^[74] This recruitment positions STAT1 for phosphorylation by associated Janus kinases, including JAK1 (primarily for type I IFNs) and JAK2 (for IFN-γ), where specific residues on JAK1/2 interact with the SH2 and kinase domains of STAT1 to facilitate tyrosine phosphorylation at Y701.^[74] Co-immunoprecipitation studies have confirmed these associations, demonstrating stable complexes in activated cells without reported dissociation constants in the nanomolar range for the direct STAT1-JAK1 interface.^[75] In dimerization, STAT1 forms heterodimers with STAT2, essential for the ISGF3 complex in type I IFN responses, where the N-terminal domains mediate high-affinity binding that is at least 1,000-fold stronger than STAT1 homodimerization, with equilibrium dissociation constants (Kd) in the low nanomolar range (e.g., ~20 nM for N-domain interactions as measured by analytical ultracentrifugation).^[76] The interface involves reciprocal phosphotyrosine-SH2 contacts (Y701 on each) and coiled-coil domain contributions for stability.^[74] STAT1 also heterodimerizes with STAT3 in contexts like IL-6 signaling, utilizing similar SH2-phosphotyrosine interfaces, though with lower affinity than STAT1-STAT2; yeast two-hybrid assays have mapped these interactions to the core DNA-binding and SH2 domains.^[74] As a transcription factor, STAT1 recruits co-factors for DNA tethering and activation. STAT1, together with STAT2, binds IRF9 (p48) to form the ISGF3 complex, with IRF9 primarily interacting with the coiled-coil domain of STAT2 and the DNA-binding domain of STAT1, with co-immunoprecipitation confirming direct association and isothermal titration calorimetry yielding a Kd of approximately 5 μM for the STAT1-IRF9 interaction.^[77] Additionally, the transactivation domain (TAD) of STAT1 directly interacts with histone acetyltransferases CBP and p300, involving two contact regions: the N-terminal domain of STAT1 with the CREB-binding domain of CBP/p300, and the C-terminal TAD with the E1A-binding domain, as demonstrated by pull-down and co-immunoprecipitation assays.^[78] Negative regulation occurs through inhibitory binding partners. PIAS1, a SUMO E3 ligase, directly associates with the STAT1 dimer (but not the tyrosine-phosphorylated monomer) via its C-terminal region, blocking DNA binding and nuclear translocation; this interaction was originally identified and confirmed by yeast two-hybrid screening and co-immunoprecipitation.^[79] SHP-1 (PTPN6), a protein tyrosine phosphatase, docks to phosphotyrosine motifs on STAT1 (and associated receptors) to catalyze dephosphorylation at Y701, terminating signaling; co-immunoprecipitation studies show SHP-1 recruitment to activated STAT1 complexes, with efficient in vitro dephosphorylation kinetics but no specific Kd reported for the docking interface.^[74]

Regulatory Networks

STAT1 activity is subject to multifaceted regulatory networks that ensure precise control over its signaling duration and specificity, involving post-translational modifications, feedback mechanisms, and pathway cross-talk. Post-translational modifications play a central role in modulating STAT1's subcellular localization and functional output. SUMOylation at lysine 703, mediated by the E3 ligase PIAS1, inhibits STAT1's DNA-binding affinity and promotes its nuclear export, thereby preventing excessive nuclear retention and attenuating interferon-induced responses. ^[80] ^[81] ^[82] In contrast, acetylation by CREB-binding protein (CBP)/p300 at lysine residues 410 and 413 in the DNA-binding domain counteracts tyrosine phosphorylation at Y701, inhibiting DNA binding and terminating STAT1 signaling to prevent prolonged activation, while also modulating interactions with other factors like NF-κB. ^[83] ^[25] ^[84] Negative feedback loops further refine STAT1 signaling to avoid hyperactivation. A prominent example is the STAT1-dependent transcription of suppressor of cytokine signaling 1 (SOCS1), which is induced following interferon stimulation and subsequently binds to Janus kinases (JAKs), inhibiting their catalytic activity and blocking further STAT1 phosphorylation. ^[85] ^[86] ^[87] Post-transcriptional regulation via microRNAs provides an additional layer of control; for instance, miR-145 directly targets the coding region of STAT1 mRNA, reducing its expression and thereby dampening pro-apoptotic or anti-proliferative effects in contexts like colon cancer. ^[88] Epigenetic mechanisms integrate STAT1 into broader chromatin regulatory networks. Upon interferon-γ stimulation, STAT1 recruits enhancer of zeste homolog 2 (EZH2), the catalytic subunit of Polycomb repressive complex 2 (PRC2), to select gene promoters, where EZH2 deposits trimethylation on histone H3 at lysine 27 (H3K27me3), enforcing transcriptional repression and modulating inflammatory gene expression.^[89] STAT1 also participates in cross-talk with other major signaling pathways, allowing integration of immune and developmental cues. Acetylation-dependent interactions with NF-κB, facilitated by CBP, inhibit NF-κB DNA binding and transcriptional activity, promoting apoptosis, while deacetylation by HDACs can shift toward antagonism. ^[83] ^[90] ^[91] These regulatory networks are attractive targets for therapeutic intervention. Small molecules such as fludarabine inhibit STAT1 nuclear import by interfering with its phosphorylation and translocation, thereby modulating excessive STAT1 activity in autoimmune diseases and enhancing chemotherapy sensitivity in cancers. ^[92] ^[93]

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Genes can have enriched specificity in different cell types in one or several tissues, or be enriched in a core cell type that appears in many different tissues ...
[11]
Epstein-Barr Virus SM Protein Functions as an Alternative Splicing ...
SM induces alternative splicing of a STAT1 mini gene. ... (A) Diagram of STAT1 minigene (DV1), which contains STAT1 exon 23, exon 24, and intervening sequence.
[12]
Tissue expression of STAT1 - Summary - The Human Protein Atlas
STAT1 is mainly expressed in lymphoid tissues, with low tissue specificity, and is part of the immune response cluster. It is detected in all tissues.
[13]
STAT1 Isoforms Differentially Regulate NK Cell Maturation and Anti ...
Two alternatively spliced isoforms of STAT1 exist: a full-length STAT1α and a C-terminally truncated STAT1β isoform. Aberrant splicing is frequently observed ...Missing: sources | Show results with:sources
[14]
144: STAT1 isoforms in transcriptional control – Distinct traits
Consistently, we found that STAT1α and STAT1β drive distinct transcriptional profiles in response to IFNγ: around half of STAT1-regulated genes were equally ...
[15]
STAT1β is not dominant negative and is capable of contributing to ...
In the absence of STAT1α, STAT1β shows more prolonged IFN-γ-induced phosphorylation and promoter binding. Both isoforms mediate protective, IFN-γ-dependent ...
[16]
p42224 · stat1_human - UniProt
The heterodimer STAT1:STAT2 forms the interferon-stimulated gene factor 3 complex (ISGF3) with IRF9 (By similarity). Interacts (phosphorylated at Ser-727) with ...
[17]
MOLECULAR BASIS FOR THE RECOGNITION OF ... - NIH
The N-terminal helical domain, roughly 130 amino acids in length ... STAT1 N-terminal domain (res. 1-132); (iii) pSTAT1 N-terminal domains do ...
[18]
Nucleocytoplasmic translocation of Stat1 is regulated by a leucine ...
... coiled-coil domain (amino acids 136–317) of Stat1. The ribbons drawing (b) shows the four-helix bundle, with amino acids 302–314 of the NES sequence in ...
[19]
The Linker Domain of Stat1 Is Required for Gamma Interferon ... - PMC
STAT dimer-dimer interaction has recently been mapped to the amino-terminal 60 to 130 amino acids (25, 26, 30). Additionally, interactions between STATs and ...Fig. 1 · Stat1(ke544-545aa) Mutants... · Fig. 8
[20]
A Conserved Motif in the Linker Domain of STAT1 Transcription ...
May 21, 2014 · In contrast, two glutamic acid residues (E559 and E563) on each monomer are important for the dissociation of dimeric STAT1 from DNA and, when ...
[21]
Dephosphorylation of phosphotyrosine on STAT1 dimers requires ...
... N-terminal domain. Claudia Mertens. Claudia Mertens. 1 Laboratory of ... First, amino acids 121–141 of STAT1 were replaced with amino acids 639–649 of MetH.
[22]
The C-Terminal Transactivation Domain of STAT1 Has a Gene ...
Moreover, transactivating activity could be transferred by fusing the 39 C-terminal amino acids to the yeast GAL4 DNA-binding domain (15–17). The STAT1 C ...
[23]
A novel interface between the N-terminal and coiled-coil domain of ...
Jul 10, 2023 · A novel interface between the N-terminal and coiled-coil domain of STAT1, specifically the E169 residue, functions in an auto-inhibitory manner ...Missing: architecture | Show results with:architecture
[24]
Tyrosine phosphorylation regulates the partitioning of STAT1 ...
Unphosphorylated STATs can dimerize in an antiparallel conformation via extended interfaces of the globular N-domains, whereas STAT activation triggers a ...
[25]
Phosphorylation meets nuclear import: a review
Dec 23, 2010 · Phosphorylation of STAT1 induces a conformational change that exposes a dimer-specific NLS ... importin β, independent of importin α [123].Missing: DBD | Show results with:DBD
[26]
Regulated nuclear import of the STAT1 transcription factor by direct ...
In this report we demonstrate a direct interaction of importin-α5 with tyrosine-phosphorylated STAT1 dimers, and provide evidence that a nuclear localization ...
[27]
A phosphorylation-acetylation switch regulates STAT1 signaling
Subsequently, STAT1 homodimers or STAT1/STAT2 heterodimers reciprocally interacting via their Src homology 2 (SH2) domains rapidly accumulate in the nucleus and ...
[28]
Protein tyrosine phosphatases as wardens of STAT signaling
... SHP-1 can attenuate JAK activation by dephosphorylation. SHP-1 (and the related PTP SHP-2) can associate through their SH2 domains with phosphorylated ...
[29]
Nuclear export signal located within theDNA-binding domain of the ...
Results indicate that STAT1 can be dephosphorylated in the nucleus and actively exported by the chromosome region maintenance 1 (CRM1) export receptor.Missing: recycling | Show results with:recycling
[30]
SHP-2 Is a Dual-specificity Phosphatase Involved in Stat1 ...
Our findings demonstrate that SHP-2 is a dual-specificity protein phosphatase involved in Stat1 dephosphorylation at both tyrosine and serine residues and plays ...Stat1 And Shp-2 Association... · Stat1 And Shp-2 Nuclear... · Stat1 C-Terminal Sh2-Ta...<|control11|><|separator|>
[31]
Mechanisms of type-I- and type-II-interferon-mediated signalling
May 1, 2005 · The transcription of type II IFN (IFN-γ)-dependent genes is regulated by GAS elements, and STAT1 is the most important IFN-γ-activated ...
[32]
The JAK/STAT signaling pathway: from bench to clinic - Nature
Nov 26, 2021 · The JAK/STAT signaling pathway was first discovered when studying how IFNs lead to the activation of a transcription factor. In 1990, the ...
[33]
Biology and significance of the JAK/STAT signalling pathways - PMC
Upon cytokine stimulation, the STATs are localised to the receptor complex by interaction of the SH2 domain with the receptor phosphotyrosine residues (Table 1) ...
[34]
Specificity of signaling by STAT1 depends on SH2 and C-terminal ...
Receptor-associated STATs are phosphorylated by JAKs on a single tyrosine residue. They dimerize by reciprocal phosphotyrosine–SH2 domain interactions, traverse ...
[35]
Regulation of STAT1 Nuclear Export by Jak1 - PMC - PubMed Central
Activation of STAT1 is achieved through its tyrosine phosphorylation, a process that involves Jak tyrosine kinases.
[36]
Constitutive and IFN-γ-induced nuclear import of STAT1 proceed ...
Nuclear import and export of unphosphorylated STAT1 are demonstrated to be sensitive towards wheat germ agglutinin and to occur independently of the import ...
[37]
Unphosphorylated STAT1 prolongs the expression of interferon ...
IFN-β and IFN-γ induced the phosphorylation of STAT1 on Y701 within 30 min in hTERT-HME1 cells, and the concentration of YP-STAT1 then decreased over the next ...Increased Stat1 Is Not... · Increased U-Stat1 Regulates... · U-Stat1 Is Required To...
[38]
Proximal protein landscapes of the type I interferon signaling ... - NIH
May 27, 2024 · Kinetic analysis of IFN-α2 signaling in MRC-5/hTERT cells revealed that critical events such as STAT1/STAT2 phosphorylation and STAT1 nuclear ...
[39]
Transcriptional regulation by STAT1 and STAT2 in the interferon ...
STAT1 and STAT2 proteins are key mediators of type I and type III interferon (IFN) signaling, and are essential components of the cellular antiviral response ...
[40]
Canonical and Non-Canonical Aspects of JAK–STAT Signaling - NIH
Jan 26, 2017 · In canonical IFN signaling, all types of IFNs produce a transcriptionally active signal transducer and activator of transcription 1 (STAT1) ...Ifns And Their Role In... · Kinase-Independent Jak... · Stat1-Independent Resistance...
[41]
Roles of Phosphatidylinositol 3-Kinase in Interferon-γ-dependent ...
We show that phosphatidylinositol 3-kinase (PI3K) and its effector kinase Akt play an important role in the serine phosphorylation of STAT1 and in the ...<|control11|><|separator|>
[42]
The oncogenic mechanisms of the Janus kinase-signal transducer ...
Jan 25, 2024 · In addition to the PI3K-AKT pathway, JAK-STAT signaling also interacts with other major signaling pathways, such as the MAPK-ERK pathway, ...
[43]
PIAS proteins promote SUMO-1 conjugation to STAT1 | Blood
Nov 1, 2003 · STAT1 signaling is negatively regulated by protein tyrosine phosphatases (PTPs), suppressors of cytokine signaling (SOCS), and protein inhibitor ...
[44]
Regulation of cytokine signaling pathways by PIAS proteins - Nature
Feb 13, 2006 · PIAS1 regulates both STAT and NF-κB signaling pathway. PIAS1 selectively inhibits a subset of STAT1- or NF-κB-dependent genes in response to IFN ...
[45]
SOCS1 is a critical checkpoint in immune homeostasis, inflammation ...
SOCS1 is the prototypical member of the SOCS family and functions in a classic negative-feedback loop to inhibit signaling in response to interferon, ...
[46]
Toward a new STATe: The role of STATs in mitochondrial function
This review summarizes recent findings that have led to our current understanding of how STATs influence mitochondrial function in health and disease.
[47]
Signal transducer and activator of transcription-1 localizes to ... - NIH
STAT1 has been shown to be involved in promoting apoptotic cell death in response to cardiac ischemia/reperfusion and has recently been shown by our laboratory ...
[48]
The STAT-ROS cycle extends IFN‑induced cancer cell apoptosis
We next found that IFN induced mitochondria respiratory complexes followed by induction of OCR, ROS, and apoptosis, which were partially blocked by STAT1/3 ...
[49]
Evolution of the JAK-STAT pathway - PMC - PubMed Central
The canonical pathway consists of JAK and STAT proteins activated by receptor ligation and inactivated by negative regulators, including SH2-containing protein ...
[50]
Evolution of JAK-STAT Pathway Components - Research journals
Our analysis has demonstrated significant expansion of JAK-STAT pathway components co-incident with the emergence of adaptive immunity.Missing: adaptations | Show results with:adaptations
[51]
Interferon-Stimulated Genes as Enhancers of Antiviral Innate ... - NIH
Translocation of ISGF3 to the nucleus allows activation of IFN-stimulated response elements (ISREs) in host antiviral genes, and induces the expression of ...<|control11|><|separator|>
[52]
A partial form of recessive STAT1 deficiency in humans - PMC
STAT1A is transcribed and spliced from 25 exons, whereas STAT1B is transcribed and spliced from the first 23 exons, ending downstream from the STAT1A exon 23 ...
[53]
IFN-γ–STAT1–iNOS Induces Myeloid Progenitors to ... - Frontiers
Sep 21, 2017 · IFN-gamma-induced MHC class II expression: transactivation of class II transactivator promoter IV by IFN regulatory factor-1 is regulated by ...
[54]
Differential activation of acute phase response factor/Stat3 and Stat1 ...
We demonstrated that two tyrosine motifs within the cytoplasmic part of the interleukin 6 signal transducer gp130 specifically mediate APRF activation.Missing: heterodimers | Show results with:heterodimers
[55]
Stat1-dependent, p53-independent expression of p21(waf1 ...
Using mouse fibroblasts lacking p53, p21(waf1), or Stat1, we found that optimal 7kchol-induced apoptosis requires p21(waf1) and Stat1 but not p53. Findings ...
[56]
Stat1-Dependent, p53-Independent Expression of p21waf1 ... - NIH
Using mouse fibroblasts lacking p53, p21waf1, or Stat1, we found that optimal 7kchol-induced apoptosis requires p21waf1 and Stat1 but not p53. Findings were ...
[57]
Interferon Family Cytokines in Obesity and Insulin Sensitivity - MDPI
... SOCS3 expression are mediated by STAT1 and STAT3. Moreover, IFN-β and IFN-γ induce SOCS isoforms leading to insulin resistance in 3T3-L1 adipocytes [101].
[58]
Interferon γ Attenuates Insulin Signaling, Lipid Storage, and ...
Previous work implicates STAT1 in SOCS1, and STAT3 in SOCS3, expression; lack of SOCS1 induction was observed in STAT1−/− cells (30). In mature SGBS adipocytes, ...
[59]
Targeted disruption of the Stat1 gene in mice reveals ... - PubMed
STAT1-deficient mice show no overt developmental abnormalities, but display a complete lack of responsiveness to either IFN alpha or IFN gamma and are highly ...Missing: vascular | Show results with:vascular
[60]
https://pmc.ncbi.nlm.nih.gov/articles/PMC8702442/
[61]
Requirement of histone deacetylase1 (HDAC1) in signal transducer ...
Jul 8, 2008 · Many known transcriptional repressors such as YY1 and RB associate and recruit the HDAC1/HDAC2 and mSin3A corepressor complexes to target gene ...
[62]
Human STAT1 gain-of-function heterozygous mutations - PMC - NIH
N-terminal domain (NTD) ... This study also revealed that GOF mutations in the STAT1 DBD might be associated with more severe clinical manifestations.
[63]
STAT1 Mutations in Autosomal Dominant Chronic Mucocutaneous ...
Jun 29, 2011 · We found that mutations affecting the CC domain of STAT1 in patients with autosomal dominant CMC lead to defective Th1 and Th17 responses, ...
[64]
New and recurrent gain-of-function STAT1 mutations in patients with ...
The T385M and R274W STAT1 mutations result in a gain of phosphorylation of STAT1. It was initially suggested that the STAT1 mutations in CMCD patients ...Results · Release Of Cytokines By... · Discussion
[65]
Gain-of-function human STAT1 mutations impair IL-17 immunity and ...
Jul 4, 2011 · Mutated IL-17F–containing homodimers and heterodimers were produced in normal amounts but were not biologically active, as they were unable to ...<|control11|><|separator|>
[66]
Heterozygous STAT1 gain-of-function mutations underlie an ...
Jun 23, 2016 · STAT1 GOF underlies a variety of infectious and autoimmune features, as well as carcinomas and aneurysms associated with a poor outcome.Abstract · Introduction · Results · Discussion<|separator|>
[67]
Autosomal dominant chronic mucocutaneous candidiasis ... - Frontiers
Patients with STAT1 functional mutations have a higher incidence of cerebral aneurysms than the healthy population, and CMC may be associated with the clinical ...
[68]
Molecular mechanism and structural basis of gain-of-function ... - NIH
Gain-of-function (GOF) mutations in the STAT1 gene are critical for the onset of chronic mucocutaneous candidiasis (CMC) disease.Missing: AIRE | Show results with:AIRE
[69]
Autoimmune Regulator Deficiency Results in a Decrease in STAT1 ...
Jul 13, 2017 · Patients with STAT1 gain-of-function (GOF) mutations also develop CMC and autoimmunity; they exhibit increased STAT1 protein levels at baseline ...
[70]
STAT1 Gain of Function, Type 1 Diabetes, and Reversal with JAK ...
Oct 7, 2020 · Ruxolitinib partially reverses functional natural killer cell deficiency in patients with signal transducer and activator of transcription 1 (STAT1) gain-of- ...
[71]
Improved outcome of HSCT in STAT1 gain-of-function disease ...
Jul 30, 2025 · Since then, it has been recognized that STAT1 GOF disease is an inborn error of immunity with severe immune dysregulation and various effects on ...Missing: loss- | Show results with:loss-<|control11|><|separator|>
[72]
An activating Stat1 mutant disrupts normal STAT4 innate lymphocyte ...
May 30, 2025 · Cells from Stat1T385M/+ mice correspondingly exhibited increased STAT1 protein expression in the majority of immune subsets (fig. S1B) ...An Activating Stat1 Mutant... · Results · Stat1 Gof Mice Display...
[73]
The human Stat1 gain-of-function T385M mutation causes ... - Frontiers
May 18, 2023 · The human Stat1 gain-of-function T385M mutation causes expansion of activated T-follicular helper/T-helper 1-like CD4 T cells and sex-biased autoimmunity.
[74]
STAT proteins: a kaleidoscope of canonical and non-canonical ... - NIH
Nov 22, 2021 · STAT proteins represent an important family of evolutionarily conserved transcription factors that play key roles in diverse biological processes.
[75]
JAK1 - STAT1 Interaction Summary - BioGRID
Affinity Capture-Western. An interaction is inferred when a bait protein is affinity captured from cell extracts by either polyclonal antibody or epitope ...
[76]
https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.2000117
[77]
Structural basis of STAT2 recognition by IRF9 reveals molecular ...
Jan 9, 2018 · We analyzed the interaction between STAT1136–713 and the IRF9–IAD by ITC and found an equilibrium dissociation constant, Kd, of 5 µM (Fig. 2C ...Missing: Kd | Show results with:Kd
[78]
Two contact regions between Stat1 and CBP/p300 in interferon γ ...
We show here that Stat1 can directly interact with the CREB-binding protein (CBP)/p300 family of transcriptional coactivators.
[79]
Inhibition of Stat1-mediated gene activation by PIAS1 - PMC - NIH
PIAS1 was identified by yeast two-hybrid screening for its ability to interact with Stat1. Sequence analysis indicates that human PIAS1 is almost identical ...
[80]
Stat1 and SUMO modification - American Society of Hematology
Nov 15, 2006 · Stat1K703R exhibited enhanced DNA binding, prolonged nuclear retention, and modest changes in the biologic response to IFN-γ, as recently ...
[81]
Quantitative SUMO proteomics identifies PIAS1 substrates involved ...
Feb 11, 2020 · Previous studies indicated that PIAS1 interacts with activated STAT1 and suppresses its binding to DNA. PIAS1 overexpression was reported in ...
[82]
Novel role and mechanism of protein inhibitor of activated STAT1 in ...
Overexpression of PIAS1 facilitates spatial learning, increases STAT1 sumoylation, decreases STAT1 DNA binding and decreased STAT1 phosphorylation at Tyr‐701.Pias1 Increases Stat1... · Pias1 Sirna Decreases Stat1... · Pias1 Sirna Impairs Spatial...<|separator|>
[83]
Acetylation of Stat1 modulates NF-κB activity - PMC - PubMed Central
The acetylation of Lys 410 and Lys 413 within the DNA-binding domain of Stat1 triggers its interaction with NF-κB p65. ... Therefore, CBP is likely to mediate ...
[84]
Regulation of STAT signaling by acetylation - PubMed - NIH
... CBP/p300. Acetylation of STAT1, STAT2, STAT3, STAT5b and STAT6 has been identified. This review will highlight acetylation on the modulation of STAT activation.
[85]
The molecular basis of JAK/STAT inhibition by SOCS1 - Nature
Apr 19, 2018 · The SOCS family of proteins are negative-feedback inhibitors of signalling induced by cytokines that act via the JAK/STAT pathway.
[86]
SOCS Regulation of the JAK/STAT Signalling Pathway - PMC - NIH
SOCS1 and SOCS3 are induced by diverse mechanisms in macrophages in response to microbial products and may be responsible for suppressing JAK/STAT signalling.
[87]
SOCS1-Negative Feedback of STAT1 Activation Is a Key Pathway in ...
In this study, we demonstrate for the first time that dsRNA activates the JAK–STAT pathway, which is negatively regulated by SOCS1, in human keratinocytes.
[88]
MicroRNA-145 Targets YES and STAT1 in Colon Cancer Cells - PMC
Jan 21, 2010 · STAT1 is best known for its pro-apoptotic role in response to interferons, but STAT1 has also been reported to have a pro-survival role in some ...
[89]
Transcriptional Synergism between NF-κB and STAT1 - ScienceDirect
The cross-talk between NF-κB and STAT1 is orchestrated by transcriptional coactivator CREB binding protein (CBP) and p300, which integrate distinct ...
[90]
STAT1-NFκB crosstalk triggered by interferon gamma regulates ...
The present data show that STAT1 and NFκB crosstalk controls melatonin production through a synergistic mechanism, disclosing a new integrative mechanism.
[91]
The Role of STAT1 for Crosstalk between Fibroblasts and Colon ...
In this study, we show that normal fibroblasts induce STAT1 signaling and restrain the growth of colon cancer cells. Genome-wide expression analysis revealed ...
[92]
Differential roles of STAT1alpha and STAT1beta in fludarabine ...
Nuclear translocation of p53 after fludarabine treatment was decreased when STAT1beta was overexpressed, and it was increased when STAT1alpha was induced.
[93]
RA-inducible gene-I induction augments STAT1 activation to ... - PNAS
Likewise, the treatment of Rig-I–transduced c-Kit+ mouse APL cells by fludarabine, a Stat1-specific inhibitor (34), down-regulated the Stat1 mRNA level (Fig. 5D) ...Ra-Inducible Gene-I... · Sign Up For Pnas Alerts · Results<|control11|><|separator|>
[94]
mTOR Modulates NLRP3 Inflammasome Activation via Nuclear ...
When rapamycin was combined with the STAT1 inhibitor fludarabine, NLRP3 inflammasome activity was restored. Taken together, these findings suggest a role for ...