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CD46

CD46, also known as membrane cofactor protein (MCP), is a type I transmembrane glycoprotein encoded by the CD46 gene on chromosome 1q32 that functions as a key regulator of the complement system.^[1] It acts as a cofactor for the serine protease factor I, facilitating the proteolytic inactivation of complement components C3b and C4b deposited on host cell surfaces, thereby protecting autologous cells from complement-mediated lysis and inflammation.^[2] This regulatory role is essential for maintaining immune homeostasis, as deficiencies or mutations in CD46 can lead to uncontrolled complement activation and associated pathologies.^[1] Structurally, CD46 consists of four extracellular complement control protein (CCP) modules, an O-glycosylated serine-threonine-proline-rich domain, a transmembrane region, and a short cytoplasmic tail, with multiple isoforms arising from alternative splicing that affect the cytoplasmic domain length and glycosylation patterns.^[1] The protein is ubiquitously expressed on the surface of nearly all human nucleated cells, with particularly high levels in tissues such as the kidney, testis, and placenta, enabling broad protection against complement attack.^[3] Its extracellular CCP domains bind C3b and C4b with high affinity, while the cytoplasmic tails interact with intracellular signaling molecules, linking complement regulation to broader cellular responses.^[1] Beyond complement regulation, CD46 serves as a cellular receptor for several pathogens, including measles virus, Neisseria species, and human herpesvirus 6, earning it the moniker "pathogen magnet" due to its exploitation by microbial invaders for host cell entry.^[4] It also modulates adaptive immunity by influencing T-cell differentiation, promoting a switch from pro-inflammatory Th1 responses to regulatory T cells (Tregs) that suppress autoimmunity.^[5] Clinically, genetic variants in CD46, including missense mutations in the CCP domains, are implicated in diseases such as atypical hemolytic uremic syndrome (aHUS), where they impair complement control and contribute to thrombotic microangiopathy, affecting approximately 10-20% of aHUS cases.^[1] Other associations include systemic lupus erythematosus, glomerulonephritis, and pregnancy complications like HELLP syndrome, underscoring CD46's multifaceted role in immune-related disorders.^[1]

Gene

Location and organization

The CD46 gene is located on the long arm of human chromosome 1 at cytogenetic band 1q32.2, within the regulators of complement activation (RCA) gene cluster.^[6] It spans approximately 43 kb and consists of 14 exons and 13 introns, with exons 2 through 5 encoding the four complement control protein (CCP) domains characteristic of the protein product.^[7] The gene was first identified in 1986 as a complement regulatory protein, initially termed membrane cofactor protein (MCP), through affinity purification of C3b-binding molecules from human peripheral blood cells.^[8] This discovery highlighted its role in protecting host cells from autologous complement attack. The genomic organization of CD46 includes a partial gene duplicate encompassing exons 1–4 upstream of the functional gene, though this duplicate shows no evidence of expression.^[6] The promoter region lacks a TATA box but features a GC-rich sequence, a reverse-oriented CAAT box, and multiple Sp1 binding sites that drive ubiquitous yet tissue-specific transcription.^[9] Regulatory single nucleotide polymorphisms (SNPs) in the promoter, such as -366A>G (rs2796268) and -652A>G (rs2796267), form haplotypes like MCPggaac, which reduce transcriptional activity and are associated with increased risk for atypical hemolytic uremic syndrome (aHUS).^[6] Mutations in the CD46 gene are a major genetic cause of aHUS, accounting for 10–20% of familial and sporadic cases, with over 50 distinct variants reported to date.^[6] These are predominantly heterozygous loss-of-function mutations, including missense (most common, ~70%), nonsense, frameshift, and splice-site alterations, with approximately 95% localized to the exons encoding the extracellular CCP domains (13 in CCP1, 9 in CCP2, 14 in CCP3, and 13 in CCP4).^[6] About 75% of these mutations result in absent protein expression due to instability or trafficking defects, while the remainder impair cofactor activity for complement factor I; recurrence after transplantation is high (up to 60%) due to the biallelic expression requirement in renal endothelium.^[3] The gene undergoes alternative splicing to produce multiple isoforms, including four major transmembrane variants.^[6]

Isoforms and expression

CD46 is produced through alternative splicing of its pre-mRNA, resulting in four major isoforms that differ primarily in their O-glycosylation sites and cytoplasmic tails. The isoforms vary in the serine-threonine-proline (STP)-rich region, where β1 isoforms contain a single O-glycosylation site and β2 isoforms contain four sites, while the cytoplasmic tails are either 16 amino acids long (cyt-1) or 23 amino acids long (cyt-2). These variations arise from the inclusion or exclusion of exons 7-9 for the STP region and exon 13 for the cytoplasmic tail, generating the combinations β1-cyt-1, β1-cyt-2, β2-cyt-1, and β2-cyt-2.^[1]^[10] CD46 exhibits ubiquitous expression on the surface of nearly all nucleated human cells, serving as a broad protector against complement-mediated damage. Expression levels are particularly elevated in epithelial cells, the placenta, and sperm, where it plays specialized roles in tissue protection and reproductive processes. For instance, in the placenta, CD46 levels are notably increased to safeguard the fetus from maternal complement attack during pregnancy.^[11]^[12]^[13] The regulation of CD46 expression involves both transcriptional and post-transcriptional mechanisms, including modulation by cytokines and developmental factors. Interferon-γ (IFN-γ), a key cytokine, upregulates CD46 surface expression on various cell types, enhancing its complement regulatory capacity and supporting immune cell functions such as T regulatory type 1 (Tr1) differentiation. Developmental factors also influence expression, particularly in reproductive tissues like the testis and placenta, where CD46 is tightly controlled to facilitate processes such as sperm-egg fusion.^[14]^[15] Quantitative expression data from the Genotype-Tissue Expression (GTEx) database reveal consistent median transcripts per million (TPM) values across tissues, underscoring its ubiquitous nature, with variations highlighting tissue-specific patterns. For example, median TPM exceeds 100 in epithelial-rich tissues like the vagina and cervix, around 50-70 in placenta, and 20-40 in immune tissues such as spleen and whole blood, indicating relatively higher expression in non-immune epithelial and reproductive sites compared to hematopoietic ones.^[16]

Structure

Extracellular domains

The extracellular region of CD46, also known as membrane cofactor protein (MCP), is primarily composed of four tandem short consensus repeats (SCRs), also referred to as Sushi domains or complement control protein (CCP) modules, located at the N-terminus.^[17] Each SCR domain spans approximately 60 amino acids and features four conserved cysteine residues that form two intramolecular disulfide bonds, stabilizing the characteristic beta-sheet-rich fold typical of CCP modules.^[18] These domains are connected by short linker regions, resulting in an overall rod-like architecture that extends about 115 Å in length, with a slight bend between SCR3 and SCR4.^[19] Following the SCR domains, the extracellular portion includes a serine/threonine-proline-rich (STP) region, which is heavily O-glycosylated and serves as a flexible stem or spacer between the ligand-binding SCRs and the transmembrane domain.^[20] The STP region's length and glycosylation extent vary due to alternative splicing in different CD46 isoforms, influencing the overall spacing and mobility of the extracellular domain.^[21] The SCR2-4 domains mediate binding to complement components C3b and C4b, with SCR3-4 playing a primary role in both interactions. Crystal structures of the human CD46 extracellular region, such as those derived from PDB entry 3O8E (in complex with adenovirus fiber knob, revealing the full SCR1-4 arrangement) and PDB entry 1CKL (focusing on the N-terminal SCR1-2), demonstrate an extended conformation suitable for ligand access.^[19]^[22] These structures also indicate potential for dimerization, as observed in crystal packing where SCR1 of one molecule interfaces with SCR4 of another, suggesting possible oligomeric states under physiological conditions.^[19]

Membrane and intracellular regions

CD46 is integrated into the plasma membrane via a single hydrophobic transmembrane helix, spanning approximately 20 amino acids, which spans residues 281–300 in the canonical isoform and anchors the protein as a type I transmembrane glycoprotein.^[3] This helical segment facilitates the orientation of the extracellular domains outward and the cytoplasmic tail inward, enabling the protein's dual role in membrane association and signal transduction without reliance on lipid modifications.^[23] Alternative splicing of the CD46 gene produces two distinct cytoplasmic tail isoforms, designated Cyt-1 and Cyt-2, which differ in length and functional motifs. Cyt-1 consists of 16 amino acids and includes phosphorylation sites targeted by casein kinase II and protein kinase C, supporting specific intracellular interactions.^[24] In contrast, Cyt-2 is longer at 23 amino acids and incorporates additional serine, threonine, and tyrosine residues that serve as substrates for phosphorylation by various kinases, such as Src family members during pathogen interactions.^[25] These isoform-specific tails share a common membrane-proximal sequence but diverge in their C-terminal regions, influencing protein trafficking and signaling specificity.^[26] Unlike GPI-anchored complement regulators such as decay-accelerating factor (DAF/CD55), CD46 entirely lacks a glycosylphosphatidylinositol (GPI) anchor, distinguishing its membrane topology and localization patterns.^[27] This transmembrane configuration promotes basolateral distribution in polarized cells and supports dynamic internalization upon ligand binding.^[28] The cytoplasmic tails of CD46 demonstrate notable evolutionary conservation across vertebrates, particularly in the signaling motifs that mediate interactions with intracellular adaptors and kinases, underscoring their role in adapting complement regulation to diverse physiological contexts.^[29] This preservation highlights the tails' importance beyond structural anchoring, facilitating conserved pathways for cellular responses to environmental cues.^[30]

Function

Complement regulation

CD46, also known as membrane cofactor protein (MCP), serves as a key regulator of the complement system by protecting host cells from autologous complement activation. It functions primarily as a cofactor for the serine protease factor I, which cleaves the opsonins C3b into iC3b and C4b into C4d, thereby inactivating these fragments and preventing the amplification of complement cascades that could lead to cell damage.^[3] This activity limits the formation of C3 and C5 convertases, ultimately inhibiting the assembly of the membrane attack complex (MAC).^[6] The regulatory function of CD46 is mediated through its extracellular complement control protein (CCP) domains, also termed short consensus repeats (SCRs). The four SCR domains exhibit binding affinity for C3b and C4b, with SCR1 contributing specifically to C4b binding, SCR2 and SCR3 to both ligands, and SCR4 showing involvement particularly in C3b interactions.^[31] These interactions occur on the surface of self-cells, where CD46 restricts complement activation initiated via both the classical and alternative pathways, ensuring that complement-mediated responses target foreign surfaces rather than host tissues.^[3] Experimental evidence from transfected cells demonstrates the potency of CD46 in complement inhibition; expression of CD46 in rodent cells significantly reduces MAC formation, providing dose-dependent protection against complement-mediated lysis compared to non-expressing controls.^[32] This protective effect correlates directly with CD46 surface density and underscores its role in maintaining immune homeostasis by confining complement activity to appropriate targets.^[32]

Cellular signaling and other roles

CD46 engages in diverse intracellular signaling pathways that extend beyond complement inhibition, influencing cellular processes such as cytoskeletal dynamics and immune modulation. The Cyt-1 isoform, characterized by its specific cytoplasmic tail, is particularly involved in these signaling events. In T lymphocytes, CD46 costimulation with CD3 triggers the relocalization of actin filaments, leading to profound morphological changes that enhance T cell activation and potentially regulate motility by reorganizing the cytoskeleton.^[33] A key function of CD46 signaling involves the promotion of immunosuppressive responses through regulatory T cells (Tregs). Ligation of CD46 on human CD4+ T cells induces the differentiation of type 1 regulatory T cells (Tr1), which secrete interleukin-10 (IL-10) and thereby suppress effector T cell proliferation and cytokine production, fostering peripheral immune tolerance. This IL-10-dependent mechanism is mediated primarily by the Cyt-1 tail and is essential for dampening inflammatory responses in various tissues.^[34]^[35] In reproductive biology, CD46 contributes to fertilization and early embryonic development. On human sperm, CD46 localizes to the inner acrosomal membrane and serves as a marker for acrosome-reacted spermatozoa, facilitating their binding to the zona pellucida of the oocyte during gamete fusion. Additionally, CD46 expression on trophoblast cells contributes to immune protection against complement-mediated damage during their invasion of the maternal endometrium, aiding in the establishment of the placenta and successful implantation.^[36]^[37] Recent investigations have uncovered CD46's role in metabolic regulation within epithelial cells, particularly through autophagy induction. In respiratory epithelial cells, CD46 engagement by pathogens or oxidative stress activates the Cyt-1 tail to recruit GOPC and initiate autophagosome formation, thereby modulating cellular metabolism to protect against apoptosis and maintain homeostasis. Studies as of 2025 have further elucidated how this pathway links complement sensing to autophagy-mediated nutrient recycling and energy balance during infection in epithelial barriers, with emerging evidence of its involvement in oncologic metabolic reprogramming.^[38]^[39]^[21]

Interactions

With complement proteins

CD46 primarily binds to the complement activation fragments C3b and C4b, which are deposited on host cell surfaces during complement activation, with a dissociation constant (K_d) of approximately 1 μM for each.^[40] These interactions occur via the complement control protein (CCP) domains 2 and 3 (also known as short consensus repeats SCR2 and SCR3) in the extracellular region of CD46, enabling it to recognize and engage covalently bound C3b and C4b specifically on self-tissues.^[41] In addition to direct ligand binding, CD46 associates with the serine protease factor I to form a multimolecular proteolytic complex on the cell surface. This association facilitates the cleavage of bound C3b into inactive iC3b and C4b into C4d, thereby limiting amplification of the complement cascade.^[6] The cofactor function requires the presence of intact CCP2 and CCP3 domains, as mutations or deletions in these regions abolish the association and subsequent proteolysis.^[41] CD46 exhibits weak interactions with C3d, a downstream degradation product of C3b generated after factor I cleavage, as well as with properdin, a positive regulator that stabilizes alternative pathway convertases; however, these bindings are of significantly lower affinity than those to C3b and C4b. In contrast, CD46 does not bind C1q, the recognition molecule of the classical pathway, nor the membrane attack complex C5b-9, setting it apart from regulators like C1 inhibitor and CD59 that target those components.^[3]

With pathogens and other molecules

CD46 serves as a cellular receptor for several pathogens, facilitating their attachment and entry into host cells. Measles virus (MV) binds to the short consensus repeats 1 and 2 (SCR1-2) of the CD46 extracellular domain, enabling viral hemagglutinin attachment and subsequent membrane fusion for infection. This interaction is specific to primate CD46 and is essential for laboratory-adapted MV strains, though wild-type isolates primarily use SLAM (CD150) as the primary receptor, with CD46 acting as a secondary entry point. Similarly, CD46 serves as the primary receptor for human herpesvirus 6A (HHV-6A) through its glycoprotein complex (gH-gL-gQ1-gQ2), promoting viral fusion and entry, particularly in CD46-expressing cells like T lymphocytes and monocytes. CD46 can also facilitate entry for HHV-6B in some cell types, though HHV-6B primarily uses CD134. CD46 isoforms influence the efficiency of HHV-6 entry, with certain cytoplasmic tails modulating post-binding signaling. Bacterial pathogens also exploit CD46 for adhesion and invasion. Neisseria gonorrhoeae and Neisseria meningitidis bind to CD46 via their type IV pili, which recognize SCR3-4 domains, allowing pilus-mediated attachment to epithelial cells and facilitating bacterial colonization of mucosal surfaces. This binding can lead to CD46 downregulation on host cells, potentially aiding immune evasion. Group A Streptococcus (Streptococcus pyogenes) interacts with CD46 on keratinocytes through its M protein, particularly the C-terminal repeat domains, enabling bacterial adherence and contributing to skin and soft tissue infections. CD46's role as a "pathogen magnet" includes its exploitation by Streptococcus pyogenes for enhanced virulence in human infections.^[42] Beyond pathogens, CD46 engages with cellular molecules to regulate adhesion and membrane organization. It associates directly with β1 integrins, such as α3β1 and α5β1, forming complexes that support cell-matrix interactions and cytoskeletal rearrangements during processes like sperm-egg fusion or epithelial invasion by pathogens. For instance, in group A Streptococcus infection, coordinated engagement of CD46 and α5β1 integrin is required for efficient bacterial entry into lung epithelial cells. Additionally, CD46 interacts with tetraspanins CD9 and CD81 within membrane microdomains, stabilizing these proteins in tetraspanin-enriched microdomains (TEMs) that facilitate signaling and pathogen entry. These associations with CD9 enhance HHV-6 infection by promoting CD46 clustering, while CD81 modulates broader membrane dynamics involving CD46.

Clinical significance

Complement-mediated diseases

Atypical hemolytic uremic syndrome (aHUS) is a complement-mediated thrombotic microangiopathy characterized by hemolytic anemia, thrombocytopenia, and acute kidney injury, where dysfunction in CD46 leads to uncontrolled alternative complement pathway activation on endothelial cells, promoting thrombosis and vascular damage.^[43] Mutations in the CD46 gene, encoding membrane cofactor protein (MCP), account for 10-15% of aHUS cases, often resulting in reduced CD46 surface expression and impaired C3b/C4b cofactor activity.^[44] These mutations are typically heterozygous and inherited in an autosomal dominant manner with incomplete penetrance, meaning not all carriers develop the disease, likely due to environmental triggers or modifier genes.^[45] A 2025 study identified a novel homozygous CD46 mutation (c.1127 + 2T > A) in a Chinese family with aHUS, causing aberrant splicing, exon skipping, and a frameshift that reduced mRNA expression to 0.78-fold and protein levels to approximately 47% of normal in patient-derived cells, thereby exacerbating complement dysregulation.^[44] CD46 dysfunction also contributes to C3 glomerulopathies, a group of renal disorders driven by persistent C3 deposition in glomeruli due to defective complement regulation; mutations in CD46 are included in genetic screening panels for these conditions alongside other regulators like CFH and CFI.^[46] Similarly, in age-related macular degeneration (AMD), particularly the dry form, CD46 dysregulation allows excessive complement activation in the retinal pigment epithelium, leading to inflammation and degeneration; CD46-deficient mouse models spontaneously develop AMD-like phenotypes with drusen-like deposits and photoreceptor loss.^[47] CD46 variants have also been implicated in HELLP syndrome, a severe pregnancy complication characterized by hemolysis, elevated liver enzymes, and low platelet count, often overlapping with thrombotic microangiopathy. Heterozygous mutations in CD46, such as the S13F variant, impair complement regulation and increase susceptibility to endothelial damage during pregnancy, contributing to disease pathogenesis in affected individuals.^[1] Therapeutic management of CD46-associated aHUS focuses on complement inhibition, with eculizumab—a monoclonal antibody targeting C5—demonstrating efficacy in preventing relapse and improving renal outcomes in patients with CD46 mutations, though lifelong treatment may be required in some cases due to high recurrence rates post-transplantation.^[43]

Infectious diseases

CD46 functions as a key cellular receptor for several pathogens, enabling their entry into host cells and contributing to infection dynamics. In the case of measles virus (MeV), CD46 serves as the primary receptor for vaccine and laboratory-adapted strains, such as the Edmonston lineage, where the viral hemagglutinin protein binds to the short consensus repeats (SCR1 and SCR2) domains of CD46 to facilitate attachment and membrane fusion.^[48] This interaction not only supports viral entry into diverse cell types, including immune cells, but also triggers intracellular signaling that promotes immunosuppression, a hallmark of MeV infection responsible for secondary complications like pneumonia and increased susceptibility to other infections.^[49] Specifically, CD46 cross-linking by MeV inhibits interleukin-12 (IL-12) production in monocytes and dendritic cells, dampening Th1 immune responses and cytokine secretion essential for antiviral defense.^[49] Although wild-type clinical isolates primarily utilize signaling lymphocyte activation molecule (SLAM/CD150) for entry, many retain the ability to engage CD46, particularly after adaptation in culture, underscoring its role in persistent infection.^[48] Vaccine evasion through mutations altering CD46 binding affinity is rare, with most failures attributed to host factors like polymorphisms in the CD46 gene rather than widespread viral resistance.^[50] Human herpesvirus 6 (HHV-6), encompassing variants A and B, also exploits CD46 as its principal receptor, binding via the viral glycoprotein complex to mediate endocytosis and infection of T lymphocytes, glial cells, and other targets.^[51] This receptor usage is critical for HHV-6 pathogenesis, as evidenced by selective downregulation of surface CD46 during active replication, which evades complement-mediated clearance and allows viral spread.^[51] In immunocompromised individuals, such as transplant recipients or those with HIV, HHV-6 reactivation via CD46 can lead to severe neurological complications, including encephalitis and meningoencephalitis, characterized by brain inflammation, seizures, and long-term cognitive deficits.^[51] Experimental models, including CD46-transgenic mice, demonstrate persistent HHV-6 DNA in the central nervous system following infection, mirroring human disease and highlighting CD46's role in facilitating neurotropism.^[52] Neisseria gonorrhoeae, the causative agent of gonorrhea, leverages CD46 to invade mucosal epithelial cells, initiating infection in the genital tract.^[25] The bacterium's type IV pili bind directly to CD46, recruiting the Src family kinase c-Yes to the invasion site, which rapidly phosphorylates CD46 at tyrosine 354 within minutes of attachment.^[25] This post-translational modification activates downstream signaling cascades, including cortical plaque formation beneath adherent bacteria, enhancing adhesion, cytoskeletal rearrangements, and bacterial internalization while suppressing autophagic killing mechanisms.^[25] Inhibition of this pathway, such as through Src kinase blockers, significantly reduces invasion efficiency, confirming CD46's essential contribution to gonococcal pathogenesis and potential antibiotic resistance.^[25] By manipulating CD46, N. gonorrhoeae not only evades innate immunity but also promotes chronic inflammation and tissue damage in urogenital infections.^[53] Altered CD46 expression in the otic capsule and stapes footplate has been implicated in the pathogenesis of otosclerosis, a progressive hearing loss disorder involving abnormal bone remodeling in the middle ear.^[54] Research indicates a unique CD46 isoform pattern in otosclerotic tissues, with upregulated expression potentially facilitating persistent measles virus infection by providing an optimal receptor environment for viral persistence in bony labyrinth cells.^[54] This hypothesis aligns with evidence of paramyxovirus-like inclusions in otosclerotic lesions and suggests that dysregulated CD46 signaling disrupts osteoid turnover, leading to focal bone resorption and fixation of the stapes.^[54] Regarding SARS-CoV-2, the virus responsible for COVID-19, no direct receptor role for CD46 has been established, as entry primarily occurs via ACE2.^[55] However, CD46's complement regulatory functions may indirectly modify disease severity by influencing endothelial injury and inflammatory cascades in severe cases; reduced membrane CD46 expression on endothelial cells has been observed, enhancing complement-mediated damage.^[56] This potential modulatory effect highlights CD46's broader involvement in pathogen-host interactions beyond direct binding.^[55]

Cancers

CD46, a complement regulatory protein, is frequently overexpressed in various malignancies, enabling tumor cells to evade complement-mediated cytotoxicity and immune surveillance. This overexpression contributes to tumor survival and progression by inhibiting the classical and alternative complement pathways, thereby protecting cancer cells from lysis by the innate immune system. In medulloblastoma, a pediatric brain tumor, CD46 is highly expressed on tumor cells, promoting survival through complement evasion and correlating with aggressive disease phenotypes. Studies have demonstrated that medulloblastoma specimens exhibit elevated CD46 levels, which facilitate resistance to complement-dependent immune attacks and support the rationale for CD46-targeted oncolytic virotherapies.^[57]^[58]^[59] In prostate cancer, CD46 upregulation is associated with advanced disease and metastasis, as highlighted in a 2025 review detailing the "multiverse" of CD46's oncologic interactions. This review synthesizes evidence linking elevated CD46 expression to malignant transformation and increased metastasizing potential, particularly in castration-resistant prostate cancer where CD46 shields tumors from complement activation. CD46's role extends to immune escape mechanisms, preventing effective antitumor responses and contributing to poor prognosis in metastatic settings.^[21]^[42] CD46 also plays a role in breast and ovarian cancers by facilitating immune escape. In breast cancer, high CD46 expression serves as an unfavorable prognostic factor, protecting tumor cells from host immune responses, including complement-dependent cytotoxicity, and is linked to worse clinical outcomes. Similarly, in ovarian cancer, tumoral CD46 promotes immune evasion by activating regulatory T cell-mediated suppression through interactions with lymphocyte cytosolic protein 1, thereby dampening antitumor immunity and supporting tumor progression.^[60]^[61]^[62] Therapeutically, CD46's overexpression in solid tumors has spurred the development of targeted agents, including antibody-drug conjugates in phase I trials. FOR46, a CD46-targeted ADC conjugated to monomethyl auristatin E, has shown preliminary activity in metastatic castration-resistant prostate cancer and other solid tumors, with acceptable safety profiles in early clinical testing. These approaches exploit CD46's tumor-selective expression to deliver cytotoxic payloads, bypassing normal tissue toxicity and enhancing antitumor efficacy.^[63]^[64]

Autoimmune and inflammatory diseases

CD46 has been implicated in the pathogenesis of multiple sclerosis (MS) through genetic polymorphisms that influence disease susceptibility and altered expression patterns on immune cells. Specific variants in the CD46 gene have been associated with increased risk of autoimmunity, including MS, by disrupting complement regulation and T-cell signaling pathways.^[6] In patients with MS, CD46 expression is reduced on T cells, particularly affecting the generation of regulatory Tr1 cells that secrete interleukin-10 (IL-10), leading to impaired immune suppression and enhanced inflammation.^[65] This reduction correlates with a shift toward pro-inflammatory Cyt2 isoform dominance, exacerbating T-cell effector functions in the central nervous system.^[66] In rheumatoid arthritis (RA), soluble CD46 (sCD46) levels are elevated in synovial fluid and serum, serving as a potential biomarker for disease activity and joint inflammation.^[67] Decreased membrane-bound CD46 expression on peripheral blood mononuclear cells and synovial tissues in RA patients contributes to unchecked complement activation, promoting synovial fibroblast proliferation and leukocyte infiltration.^[68] Dysregulated CD46 signaling in T cells from RA individuals impairs IL-10 production, sustaining chronic synovial inflammation and autoantibody-driven pathology.^[69] These alterations highlight CD46's role in balancing complement-mediated damage in arthritic joints. Systemic lupus erythematosus (SLE) involves dysregulated CD46 signaling that promotes B-cell hyperactivity and autoantibody production. In SLE patients, excessive shedding of membrane CD46 into its soluble form interferes with Th1 cell contraction, leading to persistent T-helper cell activation and enhanced B-cell stimulation.^[70] This dysregulation, often linked to CD46 genetic variants, results in hyperactive B cells that fail to undergo proper apoptosis, contributing to immune complex deposition and tissue damage.^[71] CD46's interaction with complement fragments like C3b further amplifies IFN-α-driven B-cell responses in active disease.^[72] Recent 2025 studies have strengthened associations between CD46 and inflammatory bowel disease (IBD), particularly through its expression in gut epithelial cells. CD46 is constitutively expressed on the basolateral surface of intestinal epithelium, maintaining barrier integrity and modulating inflammation during IBD flares such as in ulcerative colitis and Crohn's disease.^[73] Stable CD46 levels in inflamed mucosa support wound repair and limit complement-mediated epithelial damage, with reduced function linked to dysbiosis and chronic gut inflammation.^[74] These findings underscore CD46's protective role in epithelial homeostasis, offering potential therapeutic targets for IBD management.^[75]

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[32]
https://rupress.org/jem/article/175/6/1547/57438/Membrane-cofactor-protein-CD46-protects-cells-from
[33]
Membrane cofactor protein (CD46) protects cells from complement ...
Jun 1, 1992 · Membrane cofactor protein (CD46) protects cells from complement-mediated attack by an intrinsic mechanism. ... Down-regulation of CD46 by Piliated ...
[34]
CD46/CD3 costimulation induces morphological changes of human ...
Therefore, CD46 costimulation profoundly affects T cell behavior, and these results provide important data concerning the biology of primary human T cells.Missing: motility | Show results with:motility
[35]
CD46‐induced human Treg enhance B‐cell responses - Fuchs - 2009
Oct 30, 2009 · Although granzyme B expressed by natural Treg is important in tolerance induction in transplantation 45, the functional role of CD46-mediated ...
[36]
Ligation of TLR9 induced on human IL-10–secreting Tregs by 1α,25 ...
These data suggest that modulation of IL-10–Treg function by TLR9 ligands ... However, its capacity to regulate IL-10 synthesis and tolerance appears to be more ...
[37]
Characterization of CD46 and β1 integrin dynamics during sperm ...
Sep 26, 2016 · to fertilization and their dynamic relocation is crucial for the sperm-egg fusion. The unique presence of the membrane cofactor protein CD46 ...
[38]
Trophoblast 'pseudo-tumorigenesis': Significance and contributory ...
Much like malignant tumor invasion of host tissue, trophoblast invasion of ... trophoblast-leukocyte common (TLX) antigen, are CD46. Immunology. 1990 ...
[39]
Complement regulatory protein CD46 induces autophagy against ...
Aug 28, 2018 · ... complement-mediated lysis at sites of inflammation. Complement ... complement regulatory protein (CD46) to prevent complement ...
[40]
Epithelial Haven and Autophagy Breakout in Gonococci Infection
Jun 8, 2020 · The CD46-cyt-1/GOPC interaction is associated with the autophagosome formation complex Vps34/Beclin-1, recruiting this complex to initiate ...
[41]
The CD46-Jagged1 interaction is critical for human TH1 immunity.
... interaction is about 8μM and with this in a less tight affinity range as the interaction between CD46 and C3b (1 μM, Dr. Claire Harris, University of ...
[42]
https://pmc.ncbi.nlm.nih.gov/articles/PMC12043084/
[43]
Atypical hemolytic uremic syndrome: genetically-based insights into ...
The gene consists of 14 exons and 13 introns for a minimum length of 43 kb. ... Complement regulator CD46: genetic variants and disease associations. Hum ...Missing: span | Show results with:span<|control11|><|separator|>
[44]
Identification of a new CD46 gene mutation site in a family with ...
Sep 22, 2025 · Mutations in the CD46 gene alone are the second most common genetic abnormality in aHUS, accounting for 10–15% of cases [1]. The CD46 gene is ...
[45]
Genetic Atypical Hemolytic-Uremic Syndrome - GeneReviews - NCBI
Nov 16, 2007 · Genetic aHUS accounts for an estimated 60% of all aHUS. Individuals with genetic aHUS frequently experience relapse even after complete recovery.
[46]
C3 Glomerulopathy - GeneReviews® - NCBI Bookshelf - NIH
Jul 20, 2007 · CD46, CFH, CFHR1, CFHR5, and CFI are complement regulators. The role of DGKE in complement activation, although minimal, is believed to be ...
[47]
The Complement Regulatory Protein CD46 Deficient Mouse ...
The Complement Regulatory Protein CD46 Deficient Mouse Spontaneously Develops Dry-Type Age-Related Macular Degeneration–Like Phenotype - ScienceDirect.
[48]
Clinical Isolates of Measles Virus Use CD46 as a Cellular Receptor
Diversity of sites for measles virus binding and for inactivation of complement C3b and C4b on membrane cofactor protein CD46. J Biol Chem. 1995;270:15148 ...
[49]
Measles: immunosuppression, interleukin-12, and complement ...
Cross-linking of the cellular receptor for measles virus, the complement regulatory protein CD46, is sufficient to inhibit IL-12 production. CD46-mediated ...
[50]
Analysis of Measles Virus Binding Sites of the CD46 Gene in ...
It will be necessary to determine whether such CD46 gene alterations as G/A176 exist in a higher frequency among persons with measles vaccine failure.Missing: evasion | Show results with:evasion
[51]
CD46 Is a Cellular Receptor for Human Herpesvirus 6 - ScienceDirect
In immunocompromised patients, HHV-6 B may cause severe, often life-threatening, opportunistic infections, including encephalitis and meningo-encephalitis (18, ...
[52]
Human Herpesvirus 6A Infection in CD46 Transgenic Mice
In this study, we characterized a new model for HHV-6 infection in mice expressing the human CD46 protein. Infection of these mice with HHV-6A but not HHV-6B ...
[53]
Neisseria gonorrhoeae evades autophagic killing by ...
Feb 12, 2019 · Autophagy is induced through the CD46-cyt1/GOPC pathway and this response kills Ngo invading cells early in infection. Throughout infection, Ngo ...
[54]
Expression of measles virus receptors in otosclerotic, non ... - PubMed
Otosclerosis is a disease of disturbed osteoid turnover due to persistent measles virus infection and special CD46 receptor pattern of the otic capsule.
[55]
SARS-CoV2 drives JAK1/2-dependent local and systemic ... - NIH
Jun 9, 2020 · (D-E) The UMAP projection (D) and module (Mod) score (34) (E) of CD46 ... IL-6 is a cytokine associated with disease severity in COVID-19 ...
[56]
SARS-CoV-2 enhances complement-mediated endothelial injury via ...
Feb 13, 2025 · Membrane CRPs include CD35, CD46, CD55, and CD59 which are widely expressed in a variety of cell types for preventing complement-mediated ...Missing: modifier | Show results with:modifier
[57]
Treatment of medulloblastoma with a modified measles virus - PMC
May 21, 2010 · Importantly, we have also shown that medulloblastoma specimens removed from patients have high levels of CD46 expression. Having demonstrated ...
[58]
Medulloblastoma | UCSF Brain Tumor Center
... CD46, which is highly overexpressed by medulloblastoma and AT/RT cells. When the oncolytic virus recognizes CD46 it causes cell destruction and tumor regression ...
[59]
Efficacy of CD46-targeting chimeric Ad5/35 adenoviral gene therapy ...
CD46 protects host cells from CDC by binding to C3b, inactivating C3b and C4b, and preventing subsequent degradation by the plasma serine protease [17].Cd46 Promotes Suicide Gene... · Figure 4. Cd46 Promotes... · Cd46 Overexpression...<|control11|><|separator|>
[60]
The multiverse of CD46 and oncologic interactions - PMC
May 1, 2025 · The protein domains, exon number, and approximate sizes (in kb) are shown. Exons are represented by vertical lines on the protein domain, and ...Missing: span | Show results with:span
[61]
CD46 Expression is an unfavorable prognostic factor in breast ...
On tumor cells, CD46 may exhibit the potential to protect them from immune responses of the host. The present study aimed at evaluation of prognostic ...Missing: escape | Show results with:escape
[62]
The complement regulatory protein CD46 serves as a novel ...
Jun 10, 2024 · The expression of CD46 is stringently regulated by selective splicing, tissue-specific and malignancy-related factors.
[63]
Investigation of the enhanced antitumour potency of CD46-specific ...
Lastly, we demonstrate that tumoral CD46 activates Treg cell-mediated immune escape by binding with lymphocyte cytosolic protein 1 (Lcp1). ... Ovarian Cancer ...
[64]
Phase I, First-in-Human Study of FOR46 (FG-3246), an Immune ...
Mar 26, 2025 · FOR46, a fully human antibody conjugated to monomethyl auristatin E, targets a tumor-selective epitope of CD46, which is overexpressed in metastatic castration ...<|separator|>
[65]
Phase 1a/1b study of FOR46, an antibody drug conjugate (ADC ...
Jun 2, 2022 · FOR46, a novel ADC targeting CD46, demonstrates clinical activity in mCRPC pts, with an acceptable safety profile, similar to other MMAE-containing ADCs.
[66]
Alterations in CD46-mediated Tr1 regulatory T cells in patients ... - JCI
The reduced secretion of IL-10 by Tr1 cells from patients with MS was associated with increased expression of the Cyt2 isoform of CD46, as assessed by qRT-PCR, ...
[67]
T-cell regulation by CD46 and its relevance in multiple sclerosis - PMC
In particular, CD46 stimulation induces Tr1 cells, regulatory T cells characterized by massive production of interleukin-10 (IL-10), a potent anti-inflammatory ...
[68]
Altered Expression of Complement Regulatory Proteins CD35 ...
Aug 28, 2019 · The soluble forms of CD35, CD46, CD55, and CD59 have been implicated as biomarkers for disease activity (3, 12–14). Regulation of the balance ...
[69]
EXPRESSION OF COMPLEMENT REGULATORY MOLECULES ...
PMN from RA expressed significantly less of all the complement C3 convertase regulators (CD55, CD46, CD35), all the adhesion molecules (CD11a, CD11b, CD18) and ...<|separator|>
[70]
CD3/CD46-mediated generation of IL-10-secreting T cells is ...
CD46-induced IFNγ+/IL-10+ and IL-10+ cells are suppressive. By contrast, analysis of T cell populations from patients with inflammatory arthritis such as RA and ...
[71]
Dysregulated CD46 shedding interferes with Th1-contraction in ...
Here, we report a defect in CD46-regulated Th1 contraction in patients with systemic lupus erythematosus (SLE).
[72]
Immunologic and Genetic Contributors to CD46-Dependent Immune ...
Jul 21, 2023 · In addition to its co-factor activity, CD46 has important immune-modulatory activity. CD46 co-stimulation not only enforces IFN-γ production ...
[73]
Dysregulated CD46 shedding interferes with Th1‐contraction ... - NIH
In consequence, C3 or CD46‐deficient patients suffer from recurrent infections while dysregulation of CD46 signaling contributes to Th1 hyperactivity in ...
[74]
Gut complement system: a new frontier in microbiota-host ... - JCI
Oct 1, 2025 · CD46 is constitutively expressed basolaterally across the gut epithelium, with stable expression levels during inflammation (43), although ...
[75]
Revisiting the relationship between complement and ulcerative colitis
Sep 11, 2023 · Some components (e.g. C1q, CD46, CD55, CD59, and C6) are shown to safeguard the intestinal barrier and reduce intestinal inflammation, while ...
[76]
A Novel Role for CD46 in Wound Repair - Frontiers
CD46 interacts with and/or modulates expression of proteins required for intestinal epithelial cell layer integrity. (A,B) CD46 associates with SPAK and E- ...