Affinage

MARCHF7

E3 ubiquitin-protein ligase MARCHF7 · UniProt Q9H992

Length
704 aa
Mass
78.1 kDa
Annotated
2026-06-10
19 papers in source corpus 17 papers cited in narrative 17 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MARCHF7 (MARCH7/axotrophin) is a RING-variant domain E3 ubiquitin ligase that functions as a pleiotropic post-translational regulator, ubiquitinating diverse substrates with distinct chain linkages to control iron homeostasis, autophagy, ciliogenesis, innate immunity, and oncogenic signaling (PMID:42049018, PMID:37632749, PMID:28498859). Its own abundance is set by autoubiquitylation counteracted by compartment-specific deubiquitylases—USP9X in the cytosol and USP7 in the nucleus—which protect MARCHF7 from proteasomal degradation (PMID:18410486); USP9X further sequesters MARCHF7 away from the centrosome to limit its access to substrates such as NPHP5 (PMID:28498859). Catalysis depends on an intact C-terminal RING-variant domain and conserved catalytic residues, as ligase-dead mutants fail to ubiquitinate substrates (PMID:37337032, PMID:37054851). MARCHF7 suppresses ferroptosis through dual substrate targeting: K48-linked ubiquitination of NCOA4 at Lys42 to lower the labile iron pool, and K63-linked ubiquitination of TFR1 at Lys53 to restrict iron uptake (PMID:42049018). It controls protein homeostasis and selective autophagy by ubiquitinating ATG14 with mixed K6/K11/K63 chains to inhibit autophagy flux (PMID:37632749) and by modifying the peroxisomal protein PXMP4 at Lys20 to license NBR1-dependent pexophagy (PMID:41267209). In innate immunity, MARCHF7 degrades NLRP3 to suppress inflammasome activation and pyroptosis (PMID:37337032, PMID:38246482) and targets viral nsp16 (K27-linked) to restrict SARS-CoV-2 replication (PMID:40358464). It also degrades NPHP5 (K48) to govern ciliogenesis (PMID:28498859) and stabilizes Mdm2 via K63-linked ubiquitination to destabilize p53 (PMID:29295817). Beyond these substrate-defined roles, MARCHF7 is repeatedly implicated as an upstream promoter of cancer cell invasion and metastasis.

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2008 High

    Established how MARCHF7 protein levels are controlled, showing it is an autoubiquitylating E3 whose stability is set by compartment-specific deubiquitylases rather than constitutive expression.

    Evidence Co-IP, siRNA knockdown, overexpression and subcellular fractionation identifying USP9X (cytosol) and USP7 (nucleus)

    PMID:18410486

    Open questions at the time
    • Substrates of MARCHF7 not identified in this study
    • Functional consequence of compartment-specific stabilization unresolved
  2. 2010 Low

    First in vivo loss-of-function evidence that MARCHF7 restrains lymphocyte activation, linking it to LIF-receptor signaling and Nanog regulation.

    Evidence MARCH7 knockout mouse T cells with cell-cycle synchronization and expression profiling

    PMID:20962578

    Open questions at the time
    • No direct ubiquitination of LIF-receptor demonstrated
    • Mechanism connecting MARCHF7 to Nanog is correlative
  3. 2012 Medium

    Tied MARCHF7 to a tissue-specific developmental context, showing localized expression and K48-linked activity in spermiogenesis.

    Evidence Northern blot, in situ hybridization, IHC and linkage-specific ubiquitin immunostaining in developing spermatids

    PMID:23104140

    Open questions at the time
    • No substrate identified in spermatids
    • Functional requirement in fertility not tested genetically
  4. 2014 High

    Provided the first defined substrate and a disease-relevant role, showing MARCHF7 mono-ubiquitinates tau via its RING-variant domain to impair microtubule binding.

    Evidence Yeast two-hybrid, Co-IP, in vitro ubiquitination and microtubule-binding assays plus Alzheimer brain localization

    PMID:24905733

    Open questions at the time
    • Causal contribution to neurofibrillary tangle pathology not established
    • Loss of nuclear localization in AD brain mechanistically unexplained
  5. 2017 High

    Linked MARCHF7 to organelle biogenesis by identifying NPHP5 as a K48-ubiquitination substrate whose degradation drives cilia loss, and connected this to USP9X-mediated spatial control.

    Evidence Reciprocal Co-IP, linkage-specific ubiquitination, centrosomal localization and ciliogenesis assays

    PMID:28498859

    Open questions at the time
    • Physiological trigger for MARCHF7 centrosomal recruitment beyond USP9X loss unclear
    • In vivo ciliopathy relevance not addressed
  6. 2018 High

    Defined a substrate-specific oncogenic mechanism in which MARCHF7 K63-ubiquitinates Mdm2 to stabilize it and thereby promote p53 degradation.

    Evidence Co-IP, in vitro ubiquitination with linkage analysis and cell-based degradation/epistasis assays

    PMID:29295817

    Open questions at the time
    • Structural basis for linkage selectivity not defined
    • In vivo tumor-suppressor consequences not tested
  7. 2018 Medium

    Implicated MARCHF7 in cancer cell signaling and autophagy through TGFβR2 interaction and a proposed ceRNA mechanism controlling ATG7.

    Evidence Co-IP, ChIP, luciferase reporters and invasion/metastasis assays in ovarian cancer cells and xenografts

    PMID:29794480

    Open questions at the time
    • ceRNA mechanism is inferential, not biochemically demonstrated
    • No ubiquitination substrate identified in this pathway
  8. 2015 Medium

    Positioned MARCHF7 upstream of NF-κB and Wnt/β-catenin pathways in ovarian cancer via gain- and loss-of-function epistasis.

    Evidence siRNA knockdown, overexpression, pathway western blots and xenografts

    PMID:25895127

    Open questions at the time
    • No direct substrate linking MARCHF7 to these pathways shown
    • Mechanism of pathway activation unresolved
  9. 2018 Low

    Connected MARCHF7 to GTPase signaling by showing it interacts with VAV2 and supports VAV2-RAC1-CDC42 activity in cervical cancer.

    Evidence Single Co-IP plus pathway-level western blots after siRNA knockdown

    PMID:30008934

    Open questions at the time
    • Single Co-IP without reciprocal validation
    • No ubiquitination of VAV2 demonstrated
  10. 2019 Low

    Extended the oncogenic role to endometrial cancer via Snail-mediated EMT and identified miR-27b-3p as an upstream suppressor of MARCHF7.

    Evidence Dual-luciferase, transwell invasion, xenograft and western blot

    PMID:31006800

    Open questions at the time
    • EMT linkage is pathway-level and inferential
    • No direct enzymatic substrate identified
  11. 2023 High

    Established a direct autophagy-regulatory mechanism in which MARCHF7 ubiquitinates ATG14 with mixed chains to drive its aggregation and block autophagosome-lysosome fusion.

    Evidence Co-IP, linkage-specific ubiquitination, solubility fractionation, STX17 interaction and autophagy flux/ALIS assays

    PMID:37632749

    Open questions at the time
    • Trigger regulating MARCHF7-ATG14 targeting unknown
    • Structural basis of mixed-linkage chain assembly undefined
  12. 2023 Medium

    Identified MARCHF7 as a negative regulator of the NLRP3 inflammasome by promoting its proteasomal degradation, validated with a catalytically dead mutant.

    Evidence Co-IP, proteasome rescue, E3-dead mutant and in vivo NAFLD models

    PMID:37337032

    Open questions at the time
    • Linkage type on NLRP3 not mapped
    • Endogenous regulatory cues for NLRP3 targeting unclear
  13. 2023 Medium

    Defined an antiviral innate-immune brake, showing MARCHF7 K48-ubiquitinates TBK1 for degradation and dampens type I IFN responses, with RING domain dependence.

    Evidence Co-IP, linkage assay, RING truncation mutants and IFN reporter/viral replication assays in zebrafish

    PMID:37054851

    Open questions at the time
    • Demonstrated in zebrafish ortholog; human conservation not confirmed here
    • Context determining IFN suppression vs antiviral activity unresolved
  14. 2024 Medium

    Corroborated NLRP3 as a substrate by showing MARCHF7-mediated degradation suppresses M1 macrophage polarization and pyroptosis.

    Evidence Co-IP, siRNA rescue, ASC speck imaging and flow cytometry

    PMID:38246482

    Open questions at the time
    • Linkage type and ubiquitination site on NLRP3 not defined
    • Single-lab functional readouts
  15. 2025 Medium

    Revealed a direct antiviral effector role, with MARCHF7 K27-ubiquitinating SARS-CoV-2 nsp16 to degrade it and restrict viral replication in vivo.

    Evidence Co-IP, ubiquitination/linkage assay, proteasome rescue and cell-based and mouse replication assays

    PMID:40358464

    Open questions at the time
    • nsp16 ubiquitination site not mapped
    • Reconciliation with IFN-suppressive TBK1 role not addressed
  16. 2025 Medium

    Connected MARCHF7 to selective peroxisome autophagy by showing K20 ubiquitination of PXMP4 creates an NBR1 recognition signal, with TBK1 phosphorylating MARCHF7 as upstream control.

    Evidence Functional screen, Co-IP, K20 mutagenesis, siRNA, pexophagy flux and TBK1 phosphorylation assays

    PMID:41267209

    Open questions at the time
    • Phosphosite(s) on MARCHF7 not defined
    • Generality beyond PEX1-deficient cells untested
  17. 2026 High

    Defined the most fully resolved physiological role, showing MARCHF7 suppresses ferroptosis through site-specific dual ubiquitination of NCOA4 (K48, Lys42) and TFR1 (K63, Lys53) to lower iron availability.

    Evidence Multi-omics, in vitro ubiquitination with site-directed mutagenesis, membrane fractionation, ferroptosis assays and rodent cardioprotection models

    PMID:42049018

    Open questions at the time
    • Upstream signals coordinating dual-substrate targeting unresolved
    • How linkage selectivity for the two substrates is achieved structurally unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MARCHF7 selects among its many substrates and assembles distinct chain linkages (K27/K48/K63/mixed) in different compartments and physiological contexts remains unresolved.
  • No structural model of substrate or linkage selectivity
  • Mechanism integrating compartment-specific DUBs with substrate access not defined
  • Apparent opposing immune roles (TBK1 degradation vs antiviral nsp16/NLRP3 control) not mechanistically reconciled

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 9 GO:0016740 transferase activity 4
Localization
GO:0005634 nucleus 2 GO:0005815 microtubule organizing center 1 GO:0005829 cytosol 1
Pathway
GO:0140096 catalytic activity, acting on a protein 5
Partners
ATG14MDM2NCOA4NLRP3NPHP5PXMP4TBK1TFR1

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 MARCH7 undergoes autoubiquitylation and is stabilized by two deubiquitylating enzymes in a compartment-specific manner: USP9X deubiquitylates MARCH7 in the cytosol and USP7 deubiquitylates MARCH7 in the nucleus, preventing its proteasomal degradation. Co-immunoprecipitation, siRNA knockdown, exogenous expression, subcellular fractionation Traffic (Copenhagen, Denmark) High 18410486
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 polyubiquitination and degradation of p53. Co-immunoprecipitation, in vitro ubiquitination assay, ubiquitin linkage-specific analysis, cell-based degradation assays EMBO reports High 29295817
2014 Axotrophin/MARCH7 interacts with tau protein via amino acids 552–682 (the RING-variant domain), mono-ubiquitinates tau in vitro, and this ubiquitination diminishes tau's microtubule-binding capacity. In Alzheimer's disease brain, axotrophin loses nuclear localization and associates with neurofibrillary tangles. Yeast two-hybrid, co-immunoprecipitation, co-localization, in vitro ubiquitination assay, microtubule-binding assay Biochimica et biophysica acta High 24905733
2017 MARCH7 directly binds NPHP5 (nephrocystin-5) and K48-ubiquitinates it, triggering NPHP5 proteasomal degradation and cilia loss. USP9X sequesters MARCH7 away from the centrosome during interphase to protect NPHP5; upon USP9X depletion or inhibition, MARCH7 accumulates at the centrosome and ubiquitinates NPHP5. Co-immunoprecipitation, siRNA knockdown, ubiquitin linkage-specific analysis, immunofluorescence/localization, ciliogenesis assays PLoS genetics High 28498859
2012 MARCH7 is expressed in developing spermatids, localizes to the caudal end of the developing acrosome (co-localizing with β-actin/acroplaxome) and developing flagella, and catalyzes K48-linked ubiquitination, suggesting a role in spermiogenesis. Northern blot, in situ hybridization, immunohistochemistry, co-localization, ubiquitin linkage-specific immunostaining Histochemistry and cell biology Medium 23104140
2018 MARCH7 interacts with TGFβR2 and regulates the TGF-β-Smad2/3 signaling pathway; it also acts as a competing endogenous RNA (ceRNA) to regulate ATG7 expression by competing for miR-200a. MARCH7 silencing inhibits autophagy, invasion, and metastasis of ovarian cancer cells in vitro and in vivo. Co-immunoprecipitation, ChIP assay, luciferase reporter assay, wound healing, Matrigel invasion, orthotopic xenograft Cellular physiology and biochemistry Medium 29794480
2015 MARCH7 silencing inhibits NF-κB and Wnt/β-catenin pathways in ovarian cancer cells, and MARCH7 overexpression activates both pathways, placing MARCH7 upstream of these oncogenic cascades. siRNA knockdown, ectopic overexpression, western blot pathway analysis, in vivo xenograft Oncotarget Medium 25895127
2018 MARCH7 interacts with VAV2 and its silencing inhibits the VAV2-RAC1-CDC42 signaling pathway in cervical cancer cells, implicating MARCH7 as an upstream regulator of this GTPase cascade. Co-immunoprecipitation, siRNA knockdown, western blot pathway analysis Oncology letters Low 30008934
2019 MARCH7 promotes invasion and metastasis of endometrial cancer cells via a Snail-mediated epithelial-to-mesenchymal transition pathway, and is itself a direct target of miR-27b-3p which suppresses MARCH7 expression. Dual-luciferase reporter assay, transwell invasion assay, xenograft model, western blot Acta biochimica et biophysica Sinica Low 31006800
2023 MARCH7 ubiquitinates ATG14 with mixed K6-, K11-, and K63-linked polyubiquitin chains, triggering ATG14 aggregation and insolubility, reducing its interaction with STX17, and thereby inhibiting autophagy flux. MARCH7 depletion decreases aggresome-like induced structures (ALISs). Co-immunoprecipitation, ubiquitination assay with linkage-specific analysis, solubility fractionation, autophagy flux assay, ALIS quantification Cell reports High 37632749
2023 MARCH7 interacts with NLRP3 and promotes its proteasomal degradation via ubiquitination; a ubiquitin-ligase-inactive mutant (W589A/I556A) of MARCH7 fails to degrade NLRP3 or inhibit NAFLD. GAS5 lncRNA sequesters miR-28a-5p, which targets MARCH7 mRNA to suppress its translation. Co-immunoprecipitation, proteasome inhibitor rescue, E3-dead mutant analysis, miR target validation, in vivo NAFLD models Cell death and differentiation Medium 37337032
2023 Zebrafish MARCH7 negatively regulates type I IFN antiviral responses by interacting with TBK1 and promoting its K48-linked ubiquitination and proteasomal degradation. The C-terminal RING domain of MARCH7 is essential for TBK1 degradation and IFN suppression. Co-immunoprecipitation, ectopic expression, siRNA knockdown, ubiquitin linkage assay, RING domain truncation mutants, IFN promoter reporter assay, viral replication assay International journal of biological macromolecules Medium 37054851
2024 MARCH7 interacts with NLRP3 and mediates its ubiquitination and proteasomal degradation to suppress M1 macrophage polarization and pyroptosis. siMARCH7 transfection reversed the inhibitory effect on NLRP3 inflammasome formation. Co-immunoprecipitation, siRNA knockdown, flow cytometry, immunofluorescence (ASC speck), western blot Journal of ethnopharmacology Medium 38246482
2025 MARCHF7 promotes K27-linked ubiquitination of SARS-CoV-2 nsp16, leading to its proteasomal degradation and independently suppressing SARS-CoV-2 replication in cell cultures and in mice. Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor rescue, cell-based and in vivo viral replication assays eLife Medium 40358464
2025 MARCHF7 binds PXMP4 (a peroxisomal membrane protein) and ubiquitinates it at lysine 20 in PEX1-deficient cells, creating a recognition signal for the autophagy receptor NBR1 and driving pexophagy. TBK1 (activated by ROS upon PEX1 depletion) phosphorylates MARCHF7 to modulate this pathway. Functional screening, co-immunoprecipitation, site-directed mutagenesis (K20 mutant), siRNA knockdown, pexophagy flux assay, TBK1 phosphorylation assay Autophagy Medium 41267209
2026 MARCH7 suppresses ferroptosis via two mechanisms: (1) K48-linked ubiquitination of NCOA4 at Lys42, promoting its proteasomal degradation and reducing the labile iron pool; (2) K63-linked ubiquitination of transferrin receptor 1 (TFR1) at Lys53, restricting TFR1 plasma membrane translocation and inhibiting cellular iron uptake. Multi-omics, in vitro ubiquitination assay, site-directed mutagenesis (K42, K53), membrane fractionation, ferroptosis assays, rodent cardioprotection models Cell High 42049018
2010 MARCH7 regulates the LIF-receptor in T lymphocytes; T cells lacking MARCH7 are hyper-responsive to activation signals, show elevated LIF activity, and permit Nanog expression during G1/S phase. Addition of LIF to MARCH7-null T cells further induces Nanog ~13-fold. MARCH7 knockout mouse cells, cell cycle synchronization, transcript and protein expression analysis, miRNA profiling Cell cycle (Georgetown, Tex.) Low 20962578

Source papers

Stage 0 corpus · 19 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 58 29295817
2023 GAS5 protects against nonalcoholic fatty liver disease via miR-28a-5p/MARCH7/NLRP3 axis-mediated pyroptosis. Cell death and differentiation 56 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 MARCH7-mediated ubiquitination decreases the solubility of ATG14 to inhibit autophagy. Cell reports 12 37632749
2023 Zebrafish MARCH7 negatively regulates IFN antiviral response by degrading TBK1. International journal of biological macromolecules 10 37054851
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 6 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 3 40358464
2025 Regulation of pexophagy by a novel TBK1-MARCHF7-PXMP4-NBR1 axis in PEX1-depleted HeLa cells. Autophagy 1 41267209
2026 Stabilizing MARCH7 as a ferro-guardian against ferroptosis. Cell 0 42049018

Missed literature

Know a paper Affinage missed for MARCHF7? Flag it for the maintainers and the community.

No submissions yet.