Affinage

MARCHF7

E3 ubiquitin-protein ligase MARCHF7 · UniProt Q9H992

Length
704 aa
Mass
78.1 kDa
Annotated
2026-04-28
18 papers in source corpus 13 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MARCHF7 is a RING-variant E3 ubiquitin ligase that regulates diverse cellular processes—including ciliogenesis, autophagy, pexophagy, p53 tumor suppression, and innate immune signaling—by catalyzing substrate-specific ubiquitination with distinct linkage types. It attaches K48-linked chains to NPHP5, tau, TBK1, and NLRP3 to promote their degradation (PMID:28498859, PMID:24905733, PMID:37054851, PMID:37337032), K63-linked chains to Mdm2 to stabilize it and thereby enhance p53 degradation (PMID:29295817), mixed K6/K11/K63 chains to ATG14 to inhibit autophagy flux (PMID:37632749), and K27-linked chains to SARS-CoV-2 nsp16 for antiviral defense (PMID:40358464). MARCHF7 itself is regulated by compartment-specific deubiquitylases—USP9X in the cytosol and USP7 in the nucleus—that counteract its autoubiquitylation and control its stability and centrosomal access (PMID:18410486, PMID:28498859), and by TBK1-mediated phosphorylation that activates its pexophagy function through ubiquitination of the peroxisomal membrane protein PXMP4 (PMID:41267209).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2008 High

    Establishing that MARCHF7 is an autoubiquitylating E3 ligase whose stability is controlled by compartment-specific deubiquitylases resolved how this enzyme is itself regulated and predicted that its subcellular distribution determines substrate access.

    Evidence Co-immunoprecipitation, siRNA depletion, and subcellular fractionation in mammalian cells

    PMID:18410486

    Open questions at the time
    • Structural basis for USP9X vs. USP7 selectivity unknown
    • Endogenous substrates not yet identified at this stage
  2. 2010 Medium

    Knockout studies revealed that MARCHF7 restrains T cell activation by regulating the LIF receptor, providing the first evidence of a physiological immune-regulatory role.

    Evidence MARCH7-null mouse T cells with transcript/protein profiling

    PMID:20962578

    Open questions at the time
    • Whether LIF receptor is a direct ubiquitination substrate was not shown
    • Mechanism linking MARCHF7 loss to Nanog de-repression not fully resolved
  3. 2012 Medium

    Localization of MARCHF7 to the acrosome and developing flagella of spermatids, together with K48-linked ubiquitin catalysis, implicated the enzyme in spermiogenesis and revealed its capacity for degradative chain assembly.

    Evidence Immunohistochemistry, in situ hybridization, and linkage-specific ubiquitin assays in testis

    PMID:23104140

    Open questions at the time
    • Spermatid-specific substrates not identified
    • No loss-of-function data for fertility phenotype
  4. 2014 High

    Demonstration that MARCHF7 mono-ubiquitinates tau and reduces its microtubule-binding activity established the first biochemically reconstituted substrate and connected the enzyme to neuronal cytoskeletal regulation.

    Evidence In vitro ubiquitination assay, yeast two-hybrid, co-immunoprecipitation, microtubule-binding assay

    PMID:24905733

    Open questions at the time
    • In vivo relevance in neurons or tauopathy models not tested
    • Ubiquitin linkage type on tau not determined
  5. 2017 High

    Identification of NPHP5 as a K48-ubiquitination target and the finding that USP9X sequesters MARCHF7 away from the centrosome during interphase explained how ciliogenesis is maintained and linked MARCHF7 to ciliopathy-related biology.

    Evidence Linkage-specific ubiquitin assays, confocal localization, siRNA epistasis with USP9X and BBS11, ciliogenesis readout

    PMID:28498859

    Open questions at the time
    • Whether MARCHF7 mutations cause ciliopathies in humans is unknown
    • Mechanism of MARCHF7 release from USP9X during mitosis not resolved
  6. 2018 High

    The finding that MARCHF7 K63-ubiquitinates Mdm2 to block its self-degradation and thereby promotes p53 destruction revealed a non-degradative ubiquitin linkage output and placed MARCHF7 as a negative regulator of p53 signaling.

    Evidence In vitro ubiquitination assay, linkage-specific ubiquitin mutants, Co-IP, knockdown/overexpression

    PMID:29295817

    Open questions at the time
    • Physiological tumor context (e.g., cancer genetics) not explored
    • How MARCHF7 activity on Mdm2 is itself regulated is unclear
  7. 2018 Medium

    Studies in ovarian and cervical cancer cells linked MARCHF7 to TGFβ–Smad and VAV2–RAC1 signaling, broadening its potential roles to invasion and proliferation, though direct ubiquitination substrates in these pathways were not fully defined.

    Evidence Co-IP with TGFβR2 and VAV2, luciferase reporters, xenograft models, siRNA knockdown

    PMID:29794480 PMID:30008934

    Open questions at the time
    • VAV2 interaction rests on single Co-IP without reciprocal validation
    • Direct ubiquitination of TGFβR2 or VAV2 by MARCHF7 not demonstrated
  8. 2023 High

    Three concurrent studies defined new substrates—ATG14 (mixed K6/K11/K63 chains inhibiting autophagy flux), NLRP3 (degradative ubiquitination suppressing pyroptosis), and TBK1 (K48-linked degradation dampening type I IFN)—demonstrating MARCHF7's versatile linkage specificity and broad roles in autophagy and innate immunity.

    Evidence In vitro ubiquitination with linkage mutants, MARCHF7-KO cells, catalytic-dead mutant rescue, zebrafish viral replication assays, mouse NAFLD models

    PMID:37054851 PMID:37337032 PMID:37632749

    Open questions at the time
    • TBK1 ubiquitination demonstrated only with zebrafish ortholog; human confirmation needed
    • Structural determinants selecting among K6/K11/K48/K63 linkages unknown
    • Interplay between MARCHF7-mediated ATG14 aggregation and NLRP3 inflammasome activation not addressed
  9. 2025 High

    Identification of SARS-CoV-2 nsp16 as a K27-linked ubiquitination target and PXMP4 as a pexophagy-initiating substrate (phospho-regulated by TBK1) expanded MARCHF7's linkage repertoire further and placed it upstream of selective autophagy receptor NBR1 in peroxisome turnover.

    Evidence Linkage-specific ubiquitination assays, site-directed K20 mutagenesis of PXMP4, phosphorylation analysis, pexophagy flux assays, in vivo antiviral assays in mice

    PMID:40358464 PMID:41267209

    Open questions at the time
    • How TBK1 phosphorylation of MARCHF7 alters its substrate selectivity is mechanistically undefined
    • Relevance to peroxisomal biogenesis disorders in patients not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • A unifying structural and regulatory model explaining how MARCHF7 selects among at least five ubiquitin linkage types (K6, K11, K27, K48, K63) for different substrates remains unresolved.
  • No crystal or cryo-EM structure of MARCHF7 or its RING domain–E2 complex
  • E2 conjugating enzyme(s) partnering with MARCHF7 for each linkage type not identified
  • Upstream signals coordinating MARCHF7 activity across ciliogenesis, autophagy, and immune pathways not integrated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 10
Localization
GO:0005829 cytosol 2 GO:0005634 nucleus 1 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-392499 Metabolism of proteins 9 R-HSA-168256 Immune System 3 R-HSA-9612973 Autophagy 3 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-5357801 Programmed Cell Death 2
Partners
ATG14MDM2NLRP3NPHP5PXMP4TBK1USP7USP9X

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 MARCH7 undergoes autoubiquitylation and associates with deubiquitylating enzymes USP9X (in the cytosol) and USP7 (in the nucleus), which stabilize MARCH7 by deubiquitylating it in a compartment-specific manner. Co-immunoprecipitation, siRNA depletion, exogenous expression, subcellular fractionation Traffic High 18410486
2014 MARCH7/axotrophin interacts with tau protein via its RING-variant domain (aa 552–682) and catalyzes mono-ubiquitination of tau in vitro, which diminishes tau's microtubule-binding activity; the interaction was validated by yeast two-hybrid, co-immunoprecipitation, and co-localization. Yeast two-hybrid, co-immunoprecipitation, co-localization, in vitro ubiquitination assay, microtubule-binding assay Biochimica et biophysica acta High 24905733
2012 MARCH7 catalyzes K48-linked ubiquitination and localizes to the caudal end of the developing acrosome in spermatids (co-localizing with β-actin/acroplaxome) and to developing flagella, implicating it in spermiogenesis and sperm head/tail formation. In situ hybridization, immunohistochemistry, immunolocalization, linkage-specific ubiquitin assay Histochemistry and cell biology Medium 23104140
2017 MARCH7 directly binds NPHP5 and K48-ubiquitinates it, triggering NPHP5 degradation and cilia loss; USP9X sequesters MARCH7 away from the centrosome during interphase, and USP9X depletion allows centrosomal accumulation of MARCH7 which degrades NPHP5 to disrupt ciliogenesis. Co-immunoprecipitation, siRNA depletion, linkage-specific ubiquitin assay, confocal localization, cell cycle staging PLoS genetics High 28498859
2018 MARCH7 physically interacts with Mdm2 and catalyzes K63-linked polyubiquitination of Mdm2, which blocks Mdm2 autoubiquitination and degradation, thereby stabilizing Mdm2 and promoting Mdm2-dependent K48-linked polyubiquitination and proteasomal degradation of p53. Co-immunoprecipitation, in vitro ubiquitination assay, linkage-specific ubiquitin assay, siRNA knockdown, overexpression EMBO reports High 29295817
2018 MARCH7 interacts with TGFβR2, activates the TGF-β–Smad2/3 pathway, and promotes autophagy and invasion in ovarian cancer cells; MARCH7 also functions as a ceRNA competing with miR-200a to regulate ATG7 expression in conjunction with lncRNA MALAT1. Co-immunoprecipitation, ChIP assay, luciferase reporter assay, siRNA knockdown, overexpression, in vivo xenograft Cellular physiology and biochemistry Medium 29794480
2018 MARCH7 interacts with VAV2 and activates the VAV2–RAC1–CDC42 signaling pathway to promote proliferation and invasion of cervical cancer cells. Co-immunoprecipitation, siRNA knockdown, signaling pathway analysis Oncology letters Low 30008934
2023 MARCH7 ubiquitinates ATG14 via mixed K6-, K11-, and K63-linked polyubiquitin chains, causing ATG14 aggregation, reduced solubility, decreased interaction with STX17, and inhibition of autophagy flux; MARCH7 depletion reduces aggresome-like induced structures (ALISs). In vitro ubiquitination assay, linkage-specific ubiquitin mutants, Co-immunoprecipitation, MARCH7 knockout cells, autophagy flux assays Cell reports High 37632749
2023 MARCH7 interacts with NLRP3 and promotes its proteasomal degradation via ubiquitination; an E3 ligase-inactive MARCH7 mutant (W589A/I556A) fails to inhibit NAFLD development, establishing catalytic activity as essential for NLRP3 suppression and pyroptosis inhibition. Co-immunoprecipitation, active-site mutagenesis, siRNA knockdown, in vivo mouse models, western blot Cell death and differentiation High 37337032
2023 Zebrafish MARCH7 interacts with TBK1 via its C-terminal RING domain and promotes K48-linked ubiquitination and degradation of TBK1, thereby negatively regulating type I interferon antiviral responses. Co-immunoprecipitation, truncation mapping, siRNA knockdown, linkage-specific ubiquitin assay, viral replication assay International journal of biological macromolecules Medium 37054851
2025 Human MARCHF7 promotes K27-linked ubiquitination of SARS-CoV-2 nsp16 and its proteasomal degradation, independently suppressing viral replication in cell culture and in mice. Ubiquitination assay, proteasome inhibitor rescue, overexpression/knockdown, viral replication assay in cells and mice eLife Medium 40358464
2025 MARCHF7 binds PXMP4 and ubiquitinates it at K20 to initiate pexophagy; TBK1 (activated by ROS in PEX1-deficient cells) phosphorylates MARCHF7, and ubiquitinated PXMP4 serves as a recognition signal for NBR1 recruitment to peroxisomes. Co-immunoprecipitation, site-directed mutagenesis (K20 ubiquitination-defective mutant), siRNA knockdown, pexophagy flux assay, phosphorylation analysis Autophagy High 41267209
2010 MARCH7 regulates the LIF-receptor in T lymphocytes; T cells lacking MARCH7 are hyper-responsive to activation signals and show elevated LIF activity and permissive Nanog expression during G1/S cell cycle entry. Genetic knockout (MARCH7-null mice), miRNA profiling, transcript/protein analysis Cell cycle Medium 20962578

Source papers

Stage 0 corpus · 18 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 The ubiquitin E3 ligase MARCH7 is differentially regulated by the deubiquitylating enzymes USP7 and USP9X. Traffic (Copenhagen, Denmark) 74 18410486
2018 Regulation of the Mdm2-p53 pathway by the ubiquitin E3 ligase MARCH7. EMBO reports 57 29295817
2023 GAS5 protects against nonalcoholic fatty liver disease via miR-28a-5p/MARCH7/NLRP3 axis-mediated pyroptosis. Cell death and differentiation 54 37337032
2014 Axotrophin/MARCH7 acts as an E3 ubiquitin ligase and ubiquitinates tau protein in vitro impairing microtubule binding. Biochimica et biophysica acta 50 24905733
2018 Interaction of E3 Ubiquitin Ligase MARCH7 with Long Noncoding RNA MALAT1 and Autophagy-Related Protein ATG7 Promotes Autophagy and Invasion in Ovarian Cancer. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 48 29794480
2017 USP9X counteracts differential ubiquitination of NPHP5 by MARCH7 and BBS11 to regulate ciliogenesis. PLoS genetics 35 28498859
2019 miR-27b-3p/MARCH7 regulates invasion and metastasis of endometrial cancer cells through Snail-mediated pathway. Acta biochimica et biophysica Sinica 29 31006800
2012 MARCH7 E3 ubiquitin ligase is highly expressed in developing spermatids of rats and its possible involvement in head and tail formation. Histochemistry and cell biology 25 23104140
2015 Ubiquitin E3 ligase MARCH7 promotes ovarian tumor growth. Oncotarget 24 25895127
2018 Ubiquitin E3 Ligase MARCH7 promotes proliferation and invasion of cervical cancer cells through VAV2-RAC1-CDC42 pathway. Oncology letters 13 30008934
2023 Zebrafish MARCH7 negatively regulates IFN antiviral response by degrading TBK1. International journal of biological macromolecules 10 37054851
2023 MARCH7-mediated ubiquitination decreases the solubility of ATG14 to inhibit autophagy. Cell reports 10 37632749
2010 A LIF/Nanog axis is revealed in T lymphocytes that lack MARCH-7, a RINGv E3 ligase that regulates the LIF-receptor. Cell cycle (Georgetown, Tex.) 8 20962578
2024 Jianpi Antai formula prevents miscarriage by repressing M1 polarization of decidual macrophages through ubiquitination of NLRP3 mediated by MARCH7. Journal of ethnopharmacology 6 38246482
2023 Control of ATG14 solubility and autophagy by MARCHF7/MARCH7-mediated ubiquitination. Autophagy 5 37915253
2022 Association of MARCH7 with tumor progression and T-cell infiltration in esophageal cancer. Medical oncology (Northwood, London, England) 4 36583798
2025 SARS-CoV-2 nsp16 is regulated by host E3 ubiquitin ligases, UBR5 and MARCHF7. eLife 2 40358464
2025 Regulation of pexophagy by a novel TBK1-MARCHF7-PXMP4-NBR1 axis in PEX1-depleted HeLa cells. Autophagy 2 41267209