Affinage

UBXN7

UBX domain-containing protein 7 · UniProt O94888

Length
489 aa
Mass
54.9 kDa
Annotated
2026-06-10
10 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

UBXN7 is a multi-domain UBA-UBX adaptor that couples the p97 (VCP) AAA-ATPase segregase to ubiquitylated substrates of cullin-RING ligases, governing the turnover of regulatory proteins and the disassembly of chromatin-bound machines (PMID:18775313, PMID:35798141). It bridges substrate to segregase using independent modules: a substrate/ligase-engaging arm and a UBX domain that recruits p97, first defined for the CUL2/VHL ligase and its substrate HIF1α (PMID:18775313) and later for CUL2-LRR1-dependent ubiquitylation of the MCM7 replicative helicase, where UBXN7 serves as the substrate-specific p97 cofactor that drives replisome unloading from chromatin during S-phase (PMID:35798141). Beyond delivering substrates, UBXN7 negatively regulates ligase activity: its UIM domain binds NEDD8-modified cullins to sequester neddylated CUL2 and stabilize non-ubiquitylated HIF1α (PMID:22537386), while its UAS thioredoxin-like domain docks directly onto the RING domains of RNF111/Arkadia, RNF165 and TOPORS to block RING-E2 interaction and inhibit their autoubiquitylation, thereby stabilizing RNF111 and modulating SKIL/SnoN degradation in TGF-β signaling (PMID:37024974). As an accessory p97 adapter, UBXN7 also accelerates p97-Ufd1-Npl4-mediated substrate unfolding and proteasomal degradation by positioning the UT3 ubiquitin-binding module of Ufd1 for substrate loading (PMID:41790892). UBXN7 is itself an E3 substrate: mitochondrial MUL1 ubiquitylates UBXN7 for degradation, and loss of MUL1 elevates UBXN7, raising HIF-1α and shifting metabolism toward glycolysis, linking UBXN7 to reciprocal NRF2/HIF-1α control of oxidative versus glycolytic states (PMID:32005965, PMID:33444648). UBXN7 is additionally targeted and exploited by viral proteins, being degraded upon HBV HBx engagement and stabilizing SARS-CoV-2 N protein via its UBX domain (PMID:36096451, PMID:41086194).

Mechanistic history

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

    Established that UBXN7 is a substrate-binding adaptor connecting the p97 segregase to CRL2-mediated turnover, answering how p97 is targeted to specific ubiquitylated substrates such as HIF1α.

    Evidence Network proteomics, reciprocal co-IP, and siRNA depletion with HIF1α accumulation readout

    PMID:18775313

    Open questions at the time
    • Did not map which domains engage cullin versus p97
    • No direct demonstration that UBXN7 promotes versus restrains HIF1α degradation
  2. 2012 High

    Resolved that UBXN7 binds NEDD8-modified cullins through its UIM domain independently of its UBA module, revealing a negative-regulatory role in which sequestering neddylated CUL2 stalls CRL2 and accumulates non-ubiquitylated HIF1α.

    Evidence UIM/UBA domain mutagenesis, co-IP, overexpression assays, and MS of immunoprecipitates

    PMID:22537386

    Open questions at the time
    • Quantitative balance between adaptor (pro-degradation) and sequestration (anti-degradation) roles unresolved
    • Generality across other cullins not established here
  3. 2020 Medium

    Identified UBXN7 as a MUL1 substrate, placing mitochondrial ubiquitin signaling upstream of UBXN7 to control HIF-1α levels and the OXPHOS-to-glycolysis balance.

    Evidence MUL1 siRNA knockdown, Western blot for UBXN7/HIF-1α, and OXPHOS versus glycolysis metabolic assays

    PMID:32005965

    Open questions at the time
    • Direct MUL1-UBXN7 ubiquitylation site not mapped
    • Mechanism connecting mitochondrial localization of MUL1 to nuclear/cytosolic UBXN7 pool unclear
  4. 2021 Medium

    Extended UBXN7 to a scaffold acting on both CRL3KEAP1 and CRL2VHL, providing a reciprocal switch between NRF2 and HIF-1α outputs tied to UBXN7 abundance.

    Evidence siRNA/overexpression of UBXN7, Western blot for NRF2/HIF-1α, metabolic assays, and MUL1 inactivation

    PMID:33444648

    Open questions at the time
    • Direct structural basis for dual-CRL scaffolding not shown
    • Single-lab finding extending prior work without independent replication
  5. 2022 High

    Demonstrated that UBXN7 is the substrate-specific p97 cofactor coupling CUL2-LRR1 ubiquitylation of MCM7 to p97-driven replisome disassembly, defining a defined physiological substrate beyond HIF1α.

    Evidence Xenopus egg extract cell-free reconstitution, domain-interaction assays, and depletion/add-back monitoring replisome disassembly

    PMID:35798141

    Open questions at the time
    • Whether the same adaptor mode operates on other replication substrates not tested
    • Role of NEDD8-cullin sequestration during this process not addressed
  6. 2022 Medium

    Showed UBXN7 inhibits NF-κB signaling by binding IKKβ via its UBA domain, while being degraded through HBx-promoted K99 ubiquitylation, linking UBXN7 to inflammatory signaling and viral antagonism.

    Evidence SILAC ubiquitinome, co-IP, K99 site mutagenesis, and HBV replication assays

    PMID:36096451

    Open questions at the time
    • Identity of the E3 ligase ubiquitylating UBXN7 at K99 in the HBx context unresolved
    • Mechanism by which UBXN7 facilitates IKKβ degradation not detailed
  7. 2023 High

    Defined a distinct mechanism in which the UAS thioredoxin-like domain docks on RING E3 ligases (RNF111, RNF165, TOPORS) to block RING-E2 engagement, broadening UBXN7 from a CRL regulator to a direct RING-ligase inhibitor controlling TGF-β effector SKIL/SnoN.

    Evidence Co-IP, UAS deletion mutagenesis, UAS interactome analysis, and TGF-β-stimulated SKIL degradation assay

    PMID:37024974

    Open questions at the time
    • Structural detail of the UAS-RING interface not resolved
    • Whether this domain function is competitive with p97 adaptor activity unknown
  8. 2025 Medium

    Revealed UBXN7 engages SARS-CoV-2 N protein via its UBX domain to block K48 ubiquitylation at K257, stabilizing N and promoting viral replication, identifying a proviral exploitation of the adaptor.

    Evidence Reverse genetics, co-IP with domain mapping, K257 mutagenesis, and depletion/overexpression viral replication readouts

    PMID:41086194

    Open questions at the time
    • Whether host p97 recruitment is involved in N protein protection unclear
    • Single-lab finding without independent confirmation
  9. 2026 High

    Reconstituted that UBXN7 acts as an accessory p97 adapter that accelerates p97-Ufd1-Npl4 substrate unfolding and degradation by positioning the Ufd1 UT3 module, providing a biochemical mechanism for how it enhances segregase throughput.

    Evidence In vitro reconstituted p97-Ufd1-Npl4 unfolding/degradation assays with helix-Ufd1 interface mutagenesis and rate measurements

    PMID:41790892

    Open questions at the time
    • Whether this stimulation operates on physiological CRL2 substrates in cells not shown
    • Relationship between this accessory role and substrate-specific adaptor role not integrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How UBXN7's competing activities — p97 substrate delivery, NEDD8-cullin sequestration, and direct RING-E2 blockade — are coordinated and selectively deployed across different ligases and substrates remains unresolved.
  • No structural model integrating UIM, UBA, UAS, and UBX functions on a single ligase
  • Switching logic between pro-degradation and inhibitory modes not defined
  • In vivo physiological hierarchy of these roles not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 2 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0000228 nuclear chromosome 1
Pathway
R-HSA-1430728 Metabolism 2 R-HSA-162582 Signal Transduction 2 R-HSA-392499 Metabolism of proteins 2 R-HSA-69306 DNA Replication 1
Partners
CUL2HIF1AIKBKBMUL1RNF111TOPORSUFD1VCP
Complex memberships
CRL2LRR1CRL2VHLp97-Ufd1-Npl4 complex

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 UBXD7 (UBXN7) links p97 to the CUL2/VHL ubiquitin ligase and its substrate HIF1α; depletion of p97 leads to accumulation of endogenous HIF1α, establishing UBXN7 as a substrate-binding adaptor that connects p97 to CRL2-mediated protein turnover. Network proteomics (mass spectrometry of immunoprecipitates), co-immunoprecipitation, siRNA depletion with HIF1α accumulation readout Cell High 18775313
2012 UBXN7 directly engages NEDD8-modified cullins via its UIM (ubiquitin-interacting motif) domain, independent of its UBA ubiquitin-binding domain; this interaction is sufficient to shift CUL2 to its neddylated form and cause accumulation of non-ubiquitylated HIF1α, indicating that UBXN7 negatively regulates CRL2 ligase activity by sequestering neddylated CUL2. Mutagenesis of UIM and UBA domains, co-immunoprecipitation, over-expression assays, mass spectrometry of immunoprecipitates BMC biology High 22537386
2020 Mitochondrial MUL1 E3 ubiquitin ligase ubiquitinates UBXN7, leading to its proteasomal degradation; inactivation of MUL1 causes UBXN7 accumulation, which in turn increases HIF-1α protein levels, reduces oxidative phosphorylation, and increases glycolysis, placing MUL1 upstream of UBXN7 in the CRL2VHL pathway. siRNA knockdown of MUL1, Western blot for UBXN7 and HIF-1α, metabolic assays (OXPHOS vs. glycolysis), identification of UBXN7 as MUL1 substrate Scientific reports Medium 32005965
2021 UBXN7 acts as a scaffold for both CRL3KEAP1 and CRL2VHL complexes, mediating reciprocal regulation of NRF2 and HIF-1α: high UBXN7 levels lead to HIF-1α accumulation and glycolysis, while low UBXN7 (regulated by MUL1-mediated ubiquitination) correlates with NRF2 activation and increased OXPHOS. siRNA knockdown and overexpression of UBXN7, Western blot for NRF2 and HIF-1α, metabolic assays, MUL1 inactivation experiments Biochimica et biophysica acta. Molecular cell research Medium 33444648
2022 UBXN7 facilitates replisome disassembly during S-phase in vertebrates by coupling CUL2-LRR1-dependent ubiquitylation of MCM7 (replicative helicase) to p97-mediated unloading from chromatin; UBXN7 uses independent domains to interact with both CUL2LRR1 and p97, acting as the first substrate-specific p97 cofactor for this process. Xenopus laevis egg extract cell-free system, biochemical domain-interaction assays, depletion/add-back experiments monitoring replisome disassembly The Journal of biological chemistry High 35798141
2022 HBx protein of HBV interacts with UBXN7 to promote K48-linked ubiquitination of UBXN7 at lysine 99, leading to its proteasomal degradation; UBXN7 itself inhibits NF-κB signaling by binding the ULK domain of IKKβ via its UBA domain, facilitating IKKβ degradation. SILAC ubiquitinome analysis, Co-IP, mutagenesis (K99 site), Western blot, in vitro and in vivo HBV replication assays Cellular and molecular gastroenterology and hepatology Medium 36096451
2023 The UAS thioredoxin-like domain of UBXN7 directly docks on the RING domain of E3 ligases RNF111/Arkadia, RNF165/ARK2C, and TOPORS, inhibiting their autoubiquitylation by preventing interaction of the RING domain with E2 conjugating enzymes; this stabilizes RNF111 and modulates degradation of its substrate SKIL/SnoN in TGF-β signaling. Co-IP, domain mutagenesis (UAS deletion mutant), overexpression and siRNA depletion, interactome analysis of UAS domain, TGF-β-stimulated SKIL degradation assay BMC biology High 37024974
2026 UBXN7 (along with FAF1 and FAF2) functions as an accessory p97 adapter that boosts p97-Ufd1-Npl4-mediated substrate unfolding, thereby accelerating proteasomal degradation; stimulation occurs by positioning the UT3 ubiquitin-binding module of Ufd1 for efficient substrate loading onto p97, demonstrated by mutations in the helix-Ufd1 interaction that reduced stimulation. In vitro reconstituted p97-Ufd1-Npl4 unfolding and proteasomal degradation assay, mutagenesis of helix-Ufd1 interface, biochemical rate measurements Science advances High 41790892
2025 UBXN7 interacts with SARS-CoV-2 N protein via its UBX domain and inhibits K48-linked ubiquitination and proteasomal degradation of N protein at lysine K257, leading to N protein accumulation and promoting viral dsRNA production and genome assembly. Reverse genetics system, co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis (K257), UBXN7 depletion/overexpression with viral replication readouts PLoS pathogens Medium 41086194

Source papers

Stage 0 corpus · 10 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 UBXD7 binds multiple ubiquitin ligases and implicates p97 in HIF1alpha turnover. Cell 278 18775313
2012 UBXN7 docks on neddylated cullin complexes using its UIM motif and causes HIF1α accumulation. BMC biology 59 22537386
2020 Mitochondrial MUL1 E3 ubiquitin ligase regulates Hypoxia Inducible Factor (HIF-1α) and metabolic reprogramming by modulating the UBXN7 cofactor protein. Scientific reports 25 32005965
2021 UBXN7 cofactor of CRL3KEAP1 and CRL2VHL ubiquitin ligase complexes mediates reciprocal regulation of NRF2 and HIF-1α proteins. Biochimica et biophysica acta. Molecular cell research 20 33444648
2022 The p97 segregase cofactor Ubxn7 facilitates replisome disassembly during S-phase. The Journal of biological chemistry 15 35798141
2022 HBV X Protein Induces Degradation of UBXN7, a Novel Negative Regulator of NF-κB Signaling, to Promote HBV Replication. Cellular and molecular gastroenterology and hepatology 10 36096451
2023 The UAS thioredoxin-like domain of UBXN7 regulates E3 ubiquitin ligase activity of RNF111/Arkadia. BMC biology 3 37024974
2020 [Circular RNA-UBXN7 promotes proliferation, migration and suppresses apoptosis in hepatocellular cancer]. Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology 3 32536059
2026 The accessory adapters FAF1, FAF2, and UBXN7 accelerate proteasomal degradation by increasing prior p97-mediated substrate unfolding. Science advances 0 41790892
2025 UBXN7 facilitates SARS-CoV-2 replication via inhibiting the K48-linked ubiquitination of viral N protein. PLoS pathogens 0 41086194

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