Affinage

MARCHF8

E3 ubiquitin-protein ligase MARCHF8 · UniProt Q5T0T0

Length
291 aa
Mass
33.0 kDa
Annotated
2026-06-10
75 papers in source corpus 41 papers cited in narrative 42 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MARCHF8 (c-MIR/MARCH8) is a transmembrane RING-CH E3 ubiquitin ligase that constitutively controls the surface abundance of membrane proteins and a growing set of cytosolic and nuclear substrates, coupling target ubiquitination to lysosomal or proteasomal degradation (PMID:12582153, PMID:16785530). It was discovered through its ability to bind B7-2 (CD86) directly and route it to endocytosis and lysosomal degradation via a RING-CH (BKS-PHD) domain functionally interchangeable with viral MIR1 (PMID:12582153). A central physiological role is immune modulation: MARCHF8 ubiquitinates the MHC-II beta-chain cytoplasmic tail at a single lysine to suppress antigen presentation (PMID:16785530), and in vivo it operates specifically in non-hematopoietic cells such as thymic and alveolar epithelia—distinct from MARCH1 in hematopoietic APCs—where CD86 and MHC-II are its confirmed endogenous substrates and where it shapes CD4 T cell selection (PMID:27503071, PMID:35492398). It further tunes immune signaling by degrading immune receptors (IL1RAP via K48 linkage, IL-7Rα via K27 linkage, TRAIL-R1/DR4, FAS, TRAIL-R2/DR5) to dampen NF-κB/MAPK, IL-7/STAT5, and death-receptor apoptotic signaling (PMID:22904187, PMID:23300075, PMID:36867660, PMID:39311660). MARCHF8 is a broad antiviral effector acting through two separable mechanisms encoded in distinct regions: RING-CH–dependent ubiquitination of cytoplasmic lysines on viral envelope glycoproteins (VSV-G, IAV M2 at K78, SARS-CoV-2 spike and others) targeting them for degradation, and a C-terminal tyrosine-motif–dependent activity that traps glycoprotein/furin complexes in the trans-Golgi network, blocking glycosylation, furin cleavage, and virion incorporation (PMID:32778221, PMID:32934085, PMID:34285233, PMID:35019698, PMID:38944094, PMID:38667313). It also ubiquitinates cytosolic and nuclear regulators—cGAS at K411 (K63-linked, inhibiting cGAMP production), IFITM3 at K24, and metabolic and oncogenic factors including PTEN, STAT3, SREBP1, HK2, and NSUN6—placing it at the intersection of innate immunity, metabolism, and tumor biology (PMID:35503863, PMID:41197719, PMID:34067416, PMID:37098835, PMID:40379644). In HPV-positive head and neck cancer, MARCHF8 is transcriptionally induced and drives immune evasion by ubiquitinating MHC-I, FAS, and TRAIL receptors and by stabilizing the E7 oncoprotein through degradation of the SCF components CUL1 and UBE2L3 (PMID:36867660, PMID:38226814, PMID:41802050). Its activity is shaped by interacting regulators and modifications, including CD83 antagonism of MHC-II ubiquitination and bacterial YopJ-mediated acetylation affecting auto-ubiquitination (PMID:27503071, PMID:28103160).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2003 High

    Established MARCHF8 as a bona fide E3 ubiquitin ligase and defined its enzymatic logic—direct substrate binding plus RING-CH-catalyzed ubiquitination driving endocytosis and lysosomal degradation.

    Evidence Forced expression, ubiquitination, endocytosis/degradation assays and domain-swap mutagenesis identifying B7-2 (CD86) as substrate

    PMID:12582153

    Open questions at the time
    • Did not resolve which ubiquitin linkage types are used
    • Endogenous physiological context not addressed
  2. 2006 High

    Showed MARCHF8 controls antigen presentation by ubiquitinating MHC-II at a single defined cytoplasmic lysine, linking molecular activity to an organismal immune phenotype.

    Evidence Reconstitution with K225 mutagenesis of I-A beta-chain, transgenic mouse with impaired CD4 T cell development and EAE resistance

    PMID:16785530

    Open questions at the time
    • Tissue/cell type where endogenous MARCH8 acts on MHC-II not yet defined
    • Did not distinguish MARCH8 from MARCH1 roles
  3. 2012 High

    Extended substrate range to signaling receptors, showing MARCHF8 uses K48-linked ubiquitination to degrade IL1RAP and suppress innate inflammatory signaling.

    Evidence Co-IP, K512 mutagenesis, NF-κB/MAPK reporter assays with overexpression and knockdown

    PMID:22904187

    Open questions at the time
    • Whether IL1RAP degradation is lysosomal or proteasomal not fully resolved
  4. 2013 High

    Identified MARCHF8 as the endogenous ligase for death receptor TRAIL-R1, linking it to apoptosis regulation via a conserved membrane-proximal lysine.

    Evidence siRNA silencing, K273 mutagenesis, flow cytometry and apoptosis assays

    PMID:23300075

    Open questions at the time
    • Physiological/disease context of TRAIL-R1 control not established in this study
  5. 2016 High

    Resolved the in vivo niche of MARCHF8—non-hematopoietic thymic epithelium—and revealed CD83 as an antagonist that stabilizes MHC-II for T cell selection, establishing a division of labor with MARCH1.

    Evidence TEC reconstitution, March8/Cd83 double-KO epistasis, ubiquitination-resistant MHC-II rescue, plus bacterial SteD adaptor co-opting MARCH8 at the Golgi

    PMID:27356905 PMID:27503071 PMID:27832589

    Open questions at the time
    • Mechanism of CD83 transmembrane antagonism at atomic level unresolved
    • How pathogens redirect substrate specificity beyond adaptor binding unclear
  6. 2015 High

    Defined MARCHF8 as a host antiviral restriction factor that downregulates HIV-1 Env and broadly inhibits enveloped viruses in producer cells.

    Evidence Ectopic expression, infectivity assays, surface Env flow cytometry, Co-IP, siRNA/CRISPR KO in primary macrophages

    PMID:26523972

    Open questions at the time
    • Molecular basis of Env restriction (ubiquitination vs trafficking) not yet separated
  7. 2020 High

    Dissected two mechanistically separable antiviral activities—RING-CH ubiquitination of glycoprotein cytoplasmic lysines versus a tyrosine-motif-dependent Golgi-trapping mechanism that blocks glycosylation and furin cleavage.

    Evidence VSV-G lysine mutants and MARCH8 tyrosine-motif mutants in pseudovirus assays; BiFC, glycosylation and furin cleavage assays for EBOV GP/HIV Env/H5N1 HA

    PMID:32778221 PMID:32934085

    Open questions at the time
    • Structural basis of tyrosine-motif-mediated Golgi retention unknown
    • How the furin/glycoprotein complex is physically retained not defined
  8. 2021 High

    Confirmed substrate-specific ubiquitin linkage usage and antiviral targeting through unbiased and mechanistic approaches, including K63-linked degradation of IAV M2 and K48-linked HCV NS2 ubiquitination, while proteomics narrowed validated surface substrates to CD86 and MHC-II.

    Evidence In vivo recombinant IAV K78R virus, ubiquitination assays, MARCH8-KO mice with plasma membrane proteomics, HCV interactome screen

    PMID:30759391 PMID:34285233 PMID:35492398

    Open questions at the time
    • How linkage specificity (K48 vs K63) is determined per substrate unresolved
    • Reconciling broad overexpression substrate lists with narrow endogenous proteomic hits
  9. 2022 High

    Expanded MARCHF8 substrates beyond membrane proteins to cytosolic innate immune sensors, showing K63-linked ubiquitination of cGAS at K411 inhibits DNA sensing and cGAMP production.

    Evidence Co-IP, ubiquitination assay, K411 mutagenesis, cGAMP and DNA-binding assays, March8-KO mice with HSV-1 infection

    PMID:34572328 PMID:35019698 PMID:35503863

    Open questions at the time
    • Whether cGAS regulation is constitutive or stimulus-induced unclear
    • How a membrane-anchored ligase accesses cytosolic cGAS not addressed
  10. 2023 High

    Established MARCHF8 as a tumor-promoting effector in HPV-positive cancer that drives apoptosis resistance (FAS/TRAIL receptors) and stabilizes the E7 oncoprotein by degrading SCF components CUL1 and UBE2L3.

    Evidence Promoter reporter (MYC/MAX), Co-IP, ubiquitination assays, MARCHF8-KO in vivo tumor models, plus PTEN and PTPN4 degradation studies

    PMID:36867660 PMID:37098835 PMID:37747937 PMID:38226814

    Open questions at the time
    • Whether oncogenic vs tumor-suppressive roles are context-dependent not unified
    • Direct vs indirect contribution of each substrate to tumor phenotype unclear
  11. 2024 High

    Demonstrated MARCHF8 mediates immune evasion via MHC-I degradation and links to checkpoint immunotherapy response, while defining K27-linked degradation of IL-7Rα controlling T cell memory.

    Evidence Co-IP, ubiquitination assays, MARCHF8-KO tumor models with immune phenotyping and anti-PD-1 combination; IL-7Rα K265/K266 mutagenesis with KO mouse T cell phenotype

    PMID:38667313 PMID:39311660 PMID:39362085 PMID:41802050

    Open questions at the time
    • Determinants selecting MHC-I vs MHC-II vs other substrates unknown
    • Therapeutic targetability of MARCHF8 not established
  12. 2025 Medium

    Broadened the functional reach to metabolism, RNA modification, and additional antiviral/inflammatory pathways, including K63 ubiquitination of IFITM3, degradation of SREBP1, HK2, NSUN6, and K33-linked targeting of non-enveloped FMDV capsid proteins.

    Evidence CoIP-MS substrate ID, linkage-specific ubiquitination assays, mutagenesis of acceptor lysines, metabolomics, mitophagy and ferroptosis readouts across multiple single-lab studies

    PMID:40107011 PMID:40307900 PMID:40379644 PMID:40683951 PMID:41023307 PMID:41197719 PMID:42217319

    Open questions at the time
    • Many cytosolic/nuclear substrates rest on single-lab Co-IP plus ubiquitination without reciprocal validation
    • Physiological relevance of the very broad substrate repertoire not reconciled

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single transmembrane RING-CH ligase achieves its remarkably diverse substrate selection and chooses among K27/K33/K48/K63 linkages and lysosomal versus proteasomal fates remains unresolved.
  • No structural model of substrate recognition
  • No unifying rule linking substrate identity to ubiquitin linkage type or degradative route
  • Tissue-specific regulation of the enzyme's broad substrate set undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 6 GO:0140096 catalytic activity, acting on a protein 6 GO:0031386 protein tag activity 4
Localization
GO:0005764 lysosome 4 GO:0005886 plasma membrane 4 GO:0005794 Golgi apparatus 3
Pathway
R-HSA-1643685 Disease 6 R-HSA-168256 Immune System 6 R-HSA-392499 Metabolism of proteins 5 R-HSA-5357801 Programmed Cell Death 4 R-HSA-1430728 Metabolism 3
Partners
CD86CGASIFITM3IL1RAPIL7RMHC-IIPTENSTAT3

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 c-MIR (MARCHF8) was identified as a novel E3 ubiquitin ligase containing a BKS-PHD (RING-CH) domain. It targets B7-2 (CD86) for ubiquitination, rapid endocytosis, and lysosomal degradation by binding directly to B7-2. The BKS-PHD domain is functionally interchangeable with that of viral MIR1. Forced expression, ubiquitination assay, endocytosis and lysosomal degradation assays, domain-swap mutagenesis, binding assay The Journal of biological chemistry High 12582153
2006 c-MIR (MARCHF8) targets MHC class II (I-A beta-chain) for ubiquitination and lysosomal degradation. The ubiquitination depends on a single lysine residue (K225) in the cytoplasmic tail of the I-A beta-chain. In vivo, c-MIR overexpression in dendritic cells suppresses antigen presentation and impairs CD4 T cell development, and confers resistance to experimental autoimmune encephalomyelitis. Reconstitution in 293T cells, site-directed mutagenesis of ubiquitin acceptor lysine, forced expression in B cell lines, transgenic mouse model, flow cytometry, immunological assays Journal of immunology High 16785530
2012 MARCH8 interacts with IL-1 receptor accessory protein (IL1RAP) and catalyzes K48-linked polyubiquitination of IL1RAP at Lys512, leading to its degradation and suppression of IL-1β-induced NF-κB and MAPK activation. Overexpression of MARCH8 inhibits this signaling; knockdown has the opposite effect. Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K512), overexpression and knockdown with NF-κB/MAPK reporter assays Proceedings of the National Academy of Sciences of the United States of America High 22904187
2013 MARCH-8 ubiquitinates TRAIL-R1 (death receptor 1) at the conserved membrane-proximal lysine K273 in its cytoplasmic tail, reducing TRAIL-R1 cell surface expression and attenuating TRAIL-induced apoptosis signaling. MARCH-8 ligase activity is required for this downregulation. Gene silencing confirmed MARCH-8 as the endogenous ligase responsible. Gene silencing (siRNA), ubiquitination assay, mutagenesis of K273, flow cytometry, apoptosis assay, interaction assay The Journal of biological chemistry High 23300075
2015 MARCH8 reduces HIV-1 infectivity in virus-producing cells by downregulating HIV-1 envelope glycoprotein (Env) from the cell surface through direct interaction, thereby reducing virion incorporation of Env. MARCH8 also broadly inhibits VSV-G pseudotyped viruses. Endogenous MARCH8 is highly expressed in monocyte-derived macrophages and dendritic cells; knockdown in macrophages increases virion infectivity. Ectopic expression, HIV-1 infection assay, flow cytometry (surface Env), Co-immunoprecipitation (MARCH8-Env interaction), siRNA/CRISPR knockout, macrophage differentiation experiments Nature medicine High 26523972
2016 Salmonella effector SteD localizes to the Golgi and vesicles containing MARCH8. SteD acts as an adaptor that forces MARCH8-dependent ubiquitination of mature MHC-II (mMHCII), reducing surface mMHCII and B7.2 and suppressing T cell activation. The C-terminal cytoplasmic region of SteD binds mMHCII; its transmembrane domain binds MARCH8. Cellular localization (immunofluorescence), Co-immunoprecipitation, MARCH8-dependent ubiquitination assay, domain mapping by mutagenesis, T cell activation assay, mouse infection model Cell host & microbe High 27832589
2016 In thymic cortical epithelial cells (cTECs), MARCH8 targets MHC-II for ubiquitination and turnover. CD83's transmembrane domain antagonizes MARCH8-mediated MHC-II ubiquitination in cTECs to stabilize MHC-II, which is required for CD4 T cell selection. Ablating March8 in Cd83-/- mice rescues CD4 T cell development. There is a division of labor: MARCH1 controls MHC-II in hematopoietic APCs; MARCH8 controls constitutive MHC-II in non-hematopoietic cTECs. Viral gene reconstitution in TECs, genetic epistasis (March8/Cd83 double knockout mice), ubiquitination-resistant MHC-II variant rescue, flow cytometry of T cell populations The Journal of experimental medicine High 27503071
2016 KSHV lytic transactivator RTA upregulates MARCH8 transcription, and increased MARCH8 in turn downregulates HLA-DRα (MHC-II) surface expression, contributing to KSHV immune evasion. RTA can also directly bind and degrade HLA-DRα via the proteasome pathway independently. Overexpression, Western blot, flow cytometry, transcript analysis, KSHV de novo infection Journal of virology Medium 27356905
2017 MARCH8 mediates K48-linked ubiquitination of DR4 (TRAIL-R1/death receptor 4) at K273, leading to its degradation. JWA upregulates MARCH8 expression to promote DR4 ubiquitination, thereby suppressing TRAIL-induced apoptosis in cisplatin-resistant gastric cancer cells. Ubiquitination assay, site-directed mutagenesis, Western blot, siRNA knockdown, apoptosis assay Oncogenesis Medium 28671676
2017 Yersinia pestis acetyltransferase YopJ acetylates MARCH8 at serine (S44, S71, S253) and lysine (K247, K252) residues, and this dual acetylation affects MARCH8 auto-ubiquitination. YopJ C172A mutant abolishing acetyltransferase activity reduces acetylation and diminishes MARCH8 auto-ubiquitination. Shotgun proteomics (label-free quantification), Western blot with site-specific antibodies, in vitro acetylation assay with purified YopJ, mutagenesis (C172A) Cell cycle Medium 28103160
2019 MARCH8 catalyzes K63-linked polyubiquitination of the HCV nonstructural protein NS2 both in vitro and in HCV-infected cells, and is required for HCV envelopment. MARCH8 was identified through NS2 interactome mapping with the ubiquitin-proteasome system. Mammalian cell-based interactome screen, in vitro ubiquitination assay, HCV infection assay, Co-immunoprecipitation Cell reports High 30759391
2019 MARCH8 promotes ubiquitination and degradation of myosin light chain 2 (MLC2) in hippocampal neurons following TNF-α stimulation, contributing to caspase-3 activation and neuronal apoptosis. MARCH8 overexpression attenuates MLC2 levels; siRNA knockdown of MARCH8 blocks caspase-3 activation. In vivo intracerebroventricular TNF-α injection in rats, Western blot, siRNA knockdown, overexpression, apoptosis assay Anatomical record Low 31443122
2020 MARCH8 reduces viral infectivity via two distinct mechanisms: (1) Ubiquitination-dependent downregulation of VSV-G cytoplasmic lysine residues (lysine mutant VSV-G is resistant); (2) A tyrosine motif (cytoplasmic tyrosine motif)-dependent mechanism for HIV-1 Env (MARCH8 tyrosine motif mutant loses ability to inhibit Env-mediated infection but retains VSV-G inhibition). These are two separate pathways. Mutagenesis of VSV-G cytoplasmic lysines, mutagenesis of MARCH8 tyrosine motif, pseudovirus infection assay, ubiquitination assay eLife High 32778221
2020 MARCH8 blocks Ebola virus glycoprotein (EBOV GP) incorporation into virions by: (1) interacting with EBOV GP and furin; (2) retaining the GP/furin complex in the Golgi (BiFC assay); (3) inhibiting complex N-glycosylation of GP, O-glycosylation, and furin-mediated proteolytic cleavage. Only fully glycosylated GP is processed by furin and incorporated into virions. MARCH8 similarly blocks furin-mediated cleavage of HIV-1 Env (gp160) and H5N1 HA. Immunoprecipitation, bimolecular fluorescence complementation (BiFC) assay, glycosylation analysis, furin cleavage assay, virion incorporation assay mBio High 32934085
2021 MARCH8 mediates K63-linked polyubiquitination of influenza A virus M2 protein at lysine K78, redirecting M2 from the plasma membrane to lysosomes for degradation, thereby suppressing IAV release. A recombinant A/PR/8/34 virus carrying K78R M2 shows greater replication and pathogenicity. H1N1 IAV has evolved non-lysine residues at positions 78/79 to resist MARCH8-mediated restriction. In vitro and in vivo (mouse) infection assay, ubiquitination assay, site-directed mutagenesis (K78R), recombinant virus, lysosomal degradation assay, MARCH8 KO cells Nature communications High 34285233
2021 MARCH8 is identified as a positive regulator of type I IFN (IFN-I) signaling; SVA 2AB protein interacts with MARCHF8 and MAVS, forming a large complex that is degraded to deactivate IFN-I signaling. Additionally, 2AB degrades MARCHF8 and LC3 to inhibit autophagy. Co-immunoprecipitation, Western blot, siRNA knockdown, SVA infection assay, IFN signaling reporter assay Autophagy Medium 34964697
2021 In primary immune cells in vivo, MARCH8 (but not MARCH1) operates specifically in non-hematopoietic cells including thymic and alveolar epithelial cells to regulate MHC-II and CD86 surface expression. Only CD86 and MHC-II were confirmed as MARCH8 substrates by unbiased proteomic profiling of plasma membranes from MARCH8-deficient primary cells. MARCH8-deficient mice, unbiased proteomic profiling of plasma membranes, flow cytometry, comparison with MARCH1-deficient mice Current research in immunology High 35492398
2021 MARCH8 interacts with CD44 and mediates its lysosomal degradation. MARCH8 also ubiquitinates STAT3, a non-membrane protein, and promotes its proteasomal degradation, inducing apoptosis in breast cancer cells. Stable MARCH8 expression inhibits tumorigenesis and lung metastasis in vivo. Co-immunoprecipitation, ubiquitination assay, overexpression, xenograft mouse model, Western blot, apoptosis assay Cancers Medium 34067416
2022 MARCH8 targets cytoplasmic lysine residues of various viral envelope glycoproteins (rabies virus-G, LCMV glycoproteins, SARS-CoV and SARS-CoV-2 spike, Chikungunya E2, Ross River virus E2) for ubiquitination, intracellular degradation, and antiviral restriction. Lysine mutations in cytoplasmic tails of these glycoproteins confer resistance to MARCH8. Pseudovirus infection assay, site-directed mutagenesis of cytoplasmic lysines, immunofluorescence, ubiquitination assay Microbiology spectrum High 35019698
2022 MARCH8 interacts with the enzymatically active core of cGAS through its RING-CH domain and catalyzes K63-linked polyubiquitination of cGAS at K411. This ubiquitination inhibits cGAS DNA-binding ability and impairs cGAMP production, attenuating downstream innate immune responses. March8-deficient mice are less susceptible to HSV-1 infection. Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K411), cGAMP production assay, DNA-binding assay, MARCH8 KO mice with HSV-1 infection Science signaling High 35503863
2022 MARCH8 interacts with ABCB1 (P-glycoprotein/MDR1) and promotes its ubiquitination and degradation. Rutaecarpine upregulates MARCH8 protein levels, leading to increased ABCB1 degradation and reversal of multidrug resistance in cancer cells. Co-immunoprecipitation, ubiquitination assay, Western blot, drug cytotoxicity assay, MARCH8 overexpression Biomedicines Medium 34572328
2023 MARCH8 interacts with PTEN and promotes its ubiquitination and proteasomal degradation, activating downstream AKT signaling and promoting HCC progression. MARCH8 overexpression promotes hepatic tumor growth in vivo via the AKT pathway. Co-immunoprecipitation, ubiquitination assay, Western blot, overexpression/knockdown, xenograft mouse model, flow cytometry Molecular carcinogenesis Medium 37098835
2023 HPV E6-induced MYC/MAX transcriptional activation upregulates MARCHF8 expression in HPV-positive head and neck cancer. MARCHF8 directly interacts with and ubiquitinates FAS, TRAIL-R1 (DR4), and TRAIL-R2 (DR5), reducing their cell surface expression and inhibiting TNFRSF-mediated apoptosis. MARCHF8 KO in mouse oral cancer cells increases apoptosis and suppresses tumor growth in vivo. Promoter reporter assay, Co-immunoprecipitation, ubiquitination assay, flow cytometry, MARCHF8 KO in vivo tumor model, apoptosis assay PLoS pathogens High 36867660
2023 MARCHF8 ubiquitinates and degrades CUL1 and UBE2L3, components of the SCF ubiquitin ligase complex responsible for HPV16 E7 degradation. By degrading CUL1 and UBE2L3, MARCHF8 reduces E7 ubiquitination, stabilizing the E7 oncoprotein in HPV+ head and neck cancer cells. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, overexpression of CUL1/UBE2L3, in vivo tumor growth assay, Western blot Journal of virology High 38226814
2023 EGR1 promotes SARS-CoV-2 N protein degradation via MARCH8 ubiquitin ligase activity and cargo receptor NDP52. MARCH8 mutants lacking ubiquitin ligase activity fail to degrade the N protein, confirming E3 activity is required. Co-immunoprecipitation, MARCH8 catalytic mutant, Western blot, SARS-CoV-2 replication assay, IFN reporter Journal of virology Medium 37772822
2023 MARCH8 interacts with PTPN4 and promotes its proteasomal ubiquitination and degradation, activating STAT3 phosphorylation (pSTAT3 Y705) and promoting pancreatic cancer growth and invasion. PTPN4 overexpression suppresses STAT3 activity. Co-immunoprecipitation, ubiquitination assay, Western blot, overexpression/knockdown, xenograft mouse model Pancreas Medium 37747937
2024 MARCH8 mediates K27-linked polyubiquitination of IL-7Rα at K265/K266, leading to lysosomal degradation of IL-7Rα. This negatively regulates IL-7-triggered STAT5 activation and T cell proliferation. MARCH8 deficiency increases IL-7-triggered signaling and splenic memory CD8+ T cell differentiation in mice. Co-immunoprecipitation, ubiquitination assay with K27-linkage specificity, site-directed mutagenesis (K265/K266), MARCH8 KO mice, STAT5 reporter, T cell proliferation assay Journal of immunology High 39311660
2024 MARCH8 inhibits pseudorabies virus (PRV) replication by trapping the viral cell-to-cell fusion complex (gB, gD, gH, gL) in the trans-Golgi network, independent of its E3 ubiquitin ligase activity. MARCH8 also blocks gB cleavage by recruiting furin (a ligase-dependent activity), but the furin-blocking activity alone does not inhibit viral infection in vitro. Protein interaction assay, subcellular localization (immunofluorescence/confocal), ligase-dead MARCH8 mutant, cell-to-cell fusion assay, viral replication assay International journal of biological macromolecules Medium 38944094
2024 The antiviral function of MARCH8 requires both the RING-CH domain (for ubiquitination-dependent inhibition of VSV-G) and the C-terminal tyrosine motif (for inhibition of HIV-1 Env incorporation). Both N-terminal and C-terminal cytoplasmic tails, as well as presumably the N-terminal transmembrane domain, are critical for antiviral activity (determined by chimeric proteins between MARCH8 and non-antiviral MARCH3). MARCH8 is unable to block cell-to-cell HIV-1 infection. Chimeric protein domain analysis, mutagenesis of RING-CH and tyrosine motif, pseudovirus infection assay, cell-to-cell HIV-1 infection assay Cells Medium 38667313
2024 NLRP12 recruits MARCH8 (via its PYD domain) to the PRRSV glycoprotein GP2a, facilitating K48-linked polyubiquitination of GP2a at K128 and its lysosomal degradation via the MARCH8-NDP52 pathway, suppressing PRRSV replication. Co-immunoprecipitation (domain mapping), ubiquitination assay, site-directed mutagenesis (K128), overexpression/knockdown, viral replication assay Veterinary microbiology Medium 39362085
2024 MARCHF8 interacts with MHC-I proteins, ubiquitinates them, and promotes their degradation in HPV-positive head and neck cancer, facilitating immune evasion. MARCHF8 KO restores MHC-I levels, suppresses tumor growth, and increases NK and CD8+ T cell infiltration. Combination of MARCHF8 KO with anti-PD-1 further enhances tumor suppression in ICI-refractory tumors. Co-immunoprecipitation, ubiquitination assay, flow cytometry, MARCHF8 KO mouse tumor model, immune cell infiltration analysis, anti-PD-1 combination treatment Proceedings of the National Academy of Sciences of the United States of America High 41802050
2025 MARCH8 interacts with and promotes K63-linked polyubiquitination of IFITM3 at K24, directing it from the plasma membrane to lysosomes for degradation. MARCH8-KO cells accumulate IFITM3 at the plasma membrane after interferon treatment. MARCH8 expression attenuates IFITM3-mediated restriction of VSV and influenza A virus entry. Co-immunoprecipitation coupled to LC-MS/MS, ubiquitination assay with K63 linkage determination, site-directed mutagenesis (K24), MARCH8-KO cells, flow cytometry, viral infection assay The Journal of biological chemistry High 41197719
2025 MARCH8 ubiquitinates NSUN6 at K271 and K462, causing its proteasomal degradation. Reduced NSUN6 lowers m5C modification on PEX1 and PEX3 mRNAs, destabilizing them through loss of YBX1 binding, leading to decreased peroxisome synthesis, increased ROS, DNA damage, and increased cisplatin sensitivity. Elevated ROS enhances NSUN6-MARCH8 interaction, forming a positive feedback loop. Co-immunoprecipitation, ubiquitination assay with mutagenesis (K271/K462), m5C methylation analysis, RNA stability assay, peroxisome biogenesis assay, ROS measurement Cell death and differentiation Medium 40683951
2025 MARCH8 promotes ubiquitination and proteasomal degradation of SREBP1, suppressing key enzymes for fatty acid de novo synthesis and reducing lipid deposition in HCC. This mechanism is supported by RNA sequencing and untargeted metabolomics combined with in vivo/in vitro experiments. Co-immunoprecipitation, ubiquitination assay, RNA sequencing, untargeted metabolomics, in vivo xenograft and mouse liver cancer model Cell death & disease Medium 40379644
2025 NFATc1 transcriptionally upregulates MARCH8 in metastatic pancreatic cancer cells (where MARCH8 promoter is hypomethylated), and MARCH8 physically interacts with Orai3 intracellular loop and ubiquitinates Orai3 at its N-terminus, leading to lysosomal degradation and suppression of pancreatic cancer metastasis. In non-metastatic cells, MARCH8 promoter is hypermethylated and MARCH8 is not induced. ChIP, promoter methylation analysis, Co-immunoprecipitation, ubiquitination assay with domain mapping, overexpression/knockdown, in vivo metastasis model The EMBO journal High 41023307
2025 MARCH8 ubiquitinates CEMIP and promotes its degradation, inhibiting CRC cell proliferation, metastasis, and inducing ferroptosis through inactivation of the PI3K/AKT pathway. Overexpression of CEMIP reverses these effects. Co-immunoprecipitation, ubiquitination assay, ferroptosis markers (ROS, Fe2+, GSH, MDA), Western blot (PI3K/AKT), xenograft tumor model Pathology, research and practice Medium 40107011
2025 MARCH8 promotes K33-linked polyubiquitination of FMDV capsid proteins VP1 (at K210), VP2 (at K63), and VP3 (at K118), leading to their proteasomal degradation, thereby restricting FMDV replication in a dose-dependent manner. MARCH8 interaction and degradation of a non-enveloped virus's structural proteins demonstrates activity beyond viral envelope glycoproteins. Co-immunoprecipitation, ubiquitination assay with linkage determination, site-directed mutagenesis of substrate lysines, MARCH8 overexpression/knockdown, viral replication assay Veterinary research Medium 40307900
2025 FOXA1 transcriptionally activates MARCH8 expression; MARCH8 then catalyzes K48-linked ubiquitination of HK2 at K763, leading to HK2 degradation and inhibition of PINK1/Parkin-mediated mitophagy, thereby protecting against PM2.5-induced lung injury. ChIP (FOXA1 binding to MARCH8 promoter), Co-immunoprecipitation, ubiquitination assay with site mutagenesis (K763), mitophagy assays (mt-Keima, MMP, mtROS), in vivo mouse lung injury model Environment international Medium 42217319
2025 MARCHF8 promotes the degradation of TGFBI via ubiquitination; TGFBI in turn promotes apoptosis and ECM breakdown in LPS-stimulated nucleus pulposus cells and activates the NF-κB signaling pathway. MARCHF8 controls TGFBI expression levels, modulating intervertebral disc degeneration. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, NF-κB signaling markers, Western blot, bioinformatics (WGCNA) to identify hub gene PloS one Low 39752341
2025 MARCH8 ubiquitinates and promotes proteasomal degradation of NLRP3, and this activity is upregulated by Orientin treatment, attenuating NLRP3 inflammasome activation and pyroptosis in endothelial cells. Co-immunoprecipitation, ubiquitination assay, Western blot, NLRP3 inflammasome activation markers, in vivo atherosclerosis mouse model Mediators of inflammation Low 41891145
2024 MARCHF8 was identified as degrading MHC-I proteins via ubiquitination in HPV-positive head and neck cancer in a preprint study subsequently published (PMID 41802050). MARCHF8 knockdown restores MHC-I levels, increases NK and CD8+ T cell infiltration, and in combination with anti-PD-1 synergistically suppresses tumor growth in ICI-refractory tumors. Co-immunoprecipitation, ubiquitination assay, flow cytometry, MARCHF8 KO mouse tumor model, immune phenotyping, anti-PD-1 combination bioRxivpreprint Medium 39677690
2025 MARCH8 promotes lysosomal degradation of IFITM3 through K63-linked polyubiquitination at K24, facilitating trafficking from the plasma membrane to lysosomes; MARCH8-KO cells show plasma membrane accumulation of IFITM3 and enhanced antiviral restriction. MARCH8 expression thus counteracts IFITM3-mediated antiviral defense. Co-immunoprecipitation with LC-MS/MS, ubiquitination assay, mutagenesis (K24), flow cytometry (subcellular localization), MARCH8-KO cells, viral infection assay (VSV, IAV) The Journal of biological chemistry High 41197719

Source papers

Stage 0 corpus · 75 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 c-MIR, a human E3 ubiquitin ligase, is a functional homolog of herpesvirus proteins MIR1 and MIR2 and has similar activity. The Journal of biological chemistry 139 12582153
2015 MARCH8 inhibits HIV-1 infection by reducing virion incorporation of envelope glycoproteins. Nature medicine 128 26523972
2006 Inhibition of MHC class II expression and immune responses by c-MIR. Journal of immunology (Baltimore, Md. : 1950) 115 16785530
2012 The E3 ubiquitin ligase MARCH8 negatively regulates IL-1β-induced NF-κB activation by targeting the IL1RAP coreceptor for ubiquitination and degradation. Proceedings of the National Academy of Sciences of the United States of America 103 22904187
2016 The Salmonella Effector SteD Mediates MARCH8-Dependent Ubiquitination of MHC II Molecules and Inhibits T Cell Activation. Cell host & microbe 89 27832589
2021 MARCH8 inhibits influenza A virus infection by targeting viral M2 protein for ubiquitination-dependent degradation in lysosomes. Nature communications 77 34285233
2013 Ubiquitination by the membrane-associated RING-CH-8 (MARCH-8) ligase controls steady-state cell surface expression of tumor necrosis factor-related apoptosis inducing ligand (TRAIL) receptor 1. The Journal of biological chemistry 70 23300075
2016 Thymic CD4 T cell selection requires attenuation of March8-mediated MHCII turnover in cortical epithelial cells through CD83. The Journal of experimental medicine 67 27503071
2019 MARCH8 Ubiquitinates the Hepatitis C Virus Nonstructural 2 Protein and Mediates Viral Envelopment. Cell reports 53 30759391
2020 MARCH8 Inhibits Ebola Virus Glycoprotein, Human Immunodeficiency Virus Type 1 Envelope Glycoprotein, and Avian Influenza Virus H5N1 Hemagglutinin Maturation. mBio 52 32934085
2020 MARCH8 inhibits viral infection by two different mechanisms. eLife 50 32778221
2022 MARCH8 attenuates cGAS-mediated innate immune responses through ubiquitylation. Science signaling 48 35503863
2011 Methylation of miR-34a, miR-34b/c, miR-124-1 and miR-203 in Ph-negative myeloproliferative neoplasms. Journal of translational medicine 42 22082000
2021 2AB protein of Senecavirus A antagonizes selective autophagy and type I interferon production by degrading LC3 and MARCHF8. Autophagy 39 34964697
2022 MARCH8 Targets Cytoplasmic Lysine Residues of Various Viral Envelope Glycoproteins. Microbiology spectrum 30 35019698
2017 Increased expression of MARCH8, an E3 ubiquitin ligase, is associated with growth of esophageal tumor. Cancer cell international 30 29213217
2016 Major Histocompatibility Complex Class II HLA-DRα Is Downregulated by Kaposi's Sarcoma-Associated Herpesvirus-Encoded Lytic Transactivator RTA and MARCH8. Journal of virology 30 27356905
2021 MARCH8 Suppresses Tumor Metastasis and Mediates Degradation of STAT3 and CD44 in Breast Cancer Cells. Cancers 28 34067416
2017 JWA regulates TRAIL-induced apoptosis via MARCH8-mediated DR4 ubiquitination in cisplatin-resistant gastric cancer cells. Oncogenesis 27 28671676
2023 HPV upregulates MARCHF8 ubiquitin ligase and inhibits apoptosis by degrading the death receptors in head and neck cancer. PLoS pathogens 26 36867660
2018 Sh-MARCH8 Inhibits Tumorigenesis via PI3K Pathway in Gastric Cancer. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 23 30138931
2022 Zebrafish MARCH8 downregulates fish IFN response by targeting MITA and TBK1 for protein degradation. Developmental and comparative immunology 21 35764162
2021 HSC70 Inhibits Spring Viremia of Carp Virus Replication by Inducing MARCH8-Mediated Lysosomal Degradation of G Protein. Frontiers in immunology 19 34659210
2023 EGR1 functions as a new host restriction factor for SARS-CoV-2 to inhibit virus replication through the E3 ubiquitin ligase MARCH8. Journal of virology 18 37772822
2021 MARCH8: the tie that binds to viruses. The FEBS journal 18 33993615
2021 Rutaecarpine Increases Anticancer Drug Sensitivity in Drug-Resistant Cells through MARCH8-Dependent ABCB1 Degradation. Biomedicines 17 34572328
2023 The emerging roles of MARCH8 in viral infections: A double-edged Sword. PLoS pathogens 16 37708148
2013 Chinese multi-institutional registry (CMIR) for resected non-small cell lung cancer: survival analysis of 5,853 cases. Journal of thoracic disease 16 24409347
2022 Membrane-associated RING-CH protein (MARCH8) is a novel glycolysis repressor targeted by miR-32 in colorectal cancer. Journal of translational medicine 15 36064706
2022 Role of c-miR-21, c-miR-126, Redox Status, and Inflammatory Conditions as Potential Predictors of Vascular Damage in T2DM Patients. Antioxidants (Basel, Switzerland) 15 36139749
2018 Association Between miR-605A>G, miR-608G>C, miR-631I>D, miR-938C>T, and miR-1302-3C>T Polymorphisms and Risk of Recurrent Implantation Failure. Reproductive sciences (Thousand Oaks, Calif.) 15 29739285
2020 Study of the Association Between microRNA (miR-25T>C, miR-32C>A, miR-125C>T, and miR-222G>T) Polymorphisms and the Risk of Recurrent Pregnancy Loss in Korean Women. Genes 14 32224893
2023 Ubiquitin ligase MARCH8 promotes the malignant progression of hepatocellular carcinoma through PTEN ubiquitination and degradation. Molecular carcinogenesis 13 37098835
2019 MicroRNA-199a-5p regulates glioma progression via targeting MARCH8. European review for medical and pharmacological sciences 13 31539136
2001 Cell-mediated immune responses (CMIR) in human rhinosporidiosis. Mycopathologia 13 11761146
2021 iTRAQ-based analysis for the identification of MARCH8 targets in human esophageal squamous cell carcinoma. Journal of proteomics 12 33540066
2024 The membrane-associated ubiquitin ligase MARCHF8 stabilizes the human papillomavirus oncoprotein E7 by degrading CUL1 and UBE2L3 in head and neck cancer. Journal of virology 11 38226814
2011 Anti-arthritic effect of E3 ubiquitin ligase, c-MIR, expression in the joints. International immunology 11 21393633
2021 Physiological substrates and ontogeny-specific expression of the ubiquitin ligases MARCH1 and MARCH8. Current research in immunology 10 35492398
2019 The E3 Ubiquitin Ligase MARCH8 Regulates TNF-α-Induced Apoptosis in Hippocampal Neurons by Targeting Myosin Light Chain 2 for Degradation. Anatomical record (Hoboken, N.J. : 2007) 10 31443122
2024 MARCH8 inhibits pseudorabies virus replication by trapping the viral cell-to-cell fusion complex in the trans-Golgi network. International journal of biological macromolecules 9 38944094
2024 NLRP12 inhibits PRRSV-2 replication by promoting GP2a degradation via MARCH8. Veterinary microbiology 9 39362085
2017 Yersinia pestis acetyltransferase-mediated dual acetylation at the serine and lysine residues enhances the auto-ubiquitination of ubiquitin ligase MARCH8 in human cells. Cell cycle (Georgetown, Tex.) 9 28103160
2025 MARCH8 suppresses hepatocellular carcinoma by promoting SREBP1 degradation and modulating fatty acid de novo synthesis. Cell death & disease 7 40379644
2024 USP13 Cooperates with MARCH8 to Inhibit Antiviral Signaling by Targeting MAVS for Autophagic Degradation in Teleost. Journal of immunology (Baltimore, Md. : 1950) 7 38214605
2023 E3 Ubiquitin Ligase MARCH8 Promotes Pancreatic Cancer Growth and Metastasis by Activating STAT3 via Degradation of PTPN4. Pancreas 7 37747937
2025 miR-34a-5p/MARCHF8/ADAM10 axis in the regulation of vascular endothelial cell dysfunction and senescence. Mechanisms of ageing and development 6 40222711
2025 MARCH8/NSUN6/ROS-mediated DNA damage positive feedback loop regulates cisplatin resistance in osteosarcoma. Cell death and differentiation 6 40683951
2001 Cell-mediated immune responses (CMIR) to Rhinosporidium seeberi in mice. Mycopathologia 6 11761147
2024 DP7-C/mir-26a system promotes bone regeneration by remodeling the osteogenic immune microenvironment. Oral diseases 5 38501171
2024 OIP5-AS1 enhances the malignant characteristics and resistance to chemotherapy of pancreatic cancer cells by targeting miR-30d-5p/MARCH8. Heliyon 5 39050450
2024 MARCH8 Mediates K27-Linked Polyubiquitination of IL-7 Receptor α to Negatively Regulate IL-7-Triggered T Cell Homeostasis. Journal of immunology (Baltimore, Md. : 1950) 5 39311660
2023 Duck MARCH8 Negatively Regulates the RLR Signaling Pathway through K29-Linked Polyubiquitination of MAVS. Journal of immunology (Baltimore, Md. : 1950) 5 36715497
2025 A pan-cancer analysis of MARCH8: molecular characteristics, clinical relevance, and immuno-oncology features. Cancer biology & therapy 4 39881438
2025 MARCH8 ubiquitinates and degrades CEMIP to induce colorectal cancer cell ferroptosis through inactivating PI3K/AKT pathway. Pathology, research and practice 3 40107011
2024 MARCH8 Restricts RSV Replication by Promoting Cellular Apoptosis Through Ubiquitin-Mediated Proteolysis of Viral SH Protein. Viruses 3 39772241
2021 The Engineered MARCH8-Resistant Vesicular Stomatitis Virus Glycoprotein Enhances Lentiviral Vector Transduction. Human gene therapy 3 33678011
2025 MARCHF8-mediated ubiquitination via TGFBI regulates NF-κB dependent inflammatory responses and ECM degradation in intervertebral disc degeneration. PloS one 2 39752341
2025 NFATc1 drives Orai3 transcription and proteolysis by harnessing epigenome differences in the MARCH8 promoter. The EMBO journal 2 41023307
2024 Further Characterization of the Antiviral Transmembrane Protein MARCH8. Cells 2 38667313
2024 The membrane-associated ubiquitin ligase MARCHF8 promotes cancer immune evasion by degrading MHC class I proteins. bioRxiv : the preprint server for biology 2 39677690
2023 MARCH8 downregulation modulates profibrotic responses including myofibroblast differentiation. American journal of physiology. Cell physiology 2 37661917
2025 MARCH8 promotes the proteasomal degradation of foot-and-mouth disease virus VP1, VP2, and VP3 to negatively regulate viral replication. Veterinary research 1 40307900
2025 Novel association between E3 ubiquitin ligase MARCH8 and glucose transporter Glut1 in intracerebral hemorrhage. International immunopharmacology 1 40373593
2024 miR-335-5p Inhibits EMT and PI3K/AKT Pathways via MARCH8. Indian journal of clinical biochemistry : IJCB 1 40123623
2015 [Identification of an antiviral host transmembrane protein MARCH8]. Uirusu 1 27760915
2026 The membrane-associated ubiquitin ligase MARCHF8 degrades MHC-I in HPV-positive head and neck cancer for immune evasion. Proceedings of the National Academy of Sciences of the United States of America 0 41802050
2026 EpCAM as a novel target of MARCH8: implications for esophageal squamous cell carcinoma progression. Journal of molecular histology 0 41870734
2026 Orientin Mitigates High Glucose/Ox-LDL-Triggered Endothelial Cell Injury and Atherosclerosis by Regulating MARCH8-Mediated NLRP3 Inflammasome Activation. Mediators of inflammation 0 41891145
2026 FOXA1 protects against PM2.5-induced chronic lung injury via MARCHF8-dependent mitophagy inhibition. Environment international 0 42217319
2025 Porcine MARCH8 negatively regulates the RLR signaling pathway by targeting MAVS for protein degradation. Developmental and comparative immunology 0 40645466
2025 The E3 ubiquitin ligase MARCHF8 restricts HSV-1 infection by inhibiting replication of the viral genome. The Journal of biological chemistry 0 40780411
2025 BST-2 Promotes N Protein Degradation and Inhibits Viral Replication Through the MARCHF8/NDP52 Autophagy Pathway. Microorganisms 0 40871369
2025 MARCH8-mediated ubiquitination regulates expression of the antiviral protein IFITM3. The Journal of biological chemistry 0 41197719
2023 The membrane-associated ubiquitin ligase MARCHF8 stabilizes the human papillomavirus oncoprotein E7 by degrading CUL1 and UBE2L3 in head and neck cancer. bioRxiv : the preprint server for biology 0 37961092

Missed literature

Know a paper Affinage missed for MARCHF8? Flag it for the maintainers and the community.

No submissions yet.