USP43

USP43 is a deubiquitinating enzyme that removes K48-linked polyubiquitin chains from a broad and growing set of substrates, thereby stabilizing them and modulating transcription, signaling, metabolism, and innate immunity. In the nucleus, USP43 associates with the NuRD chromatin-remodeling complex and catalyzes H2BK120 deubiquitination, coordinating transcriptional repression of proliferative genes including EGFR (PMID:30135474); it also facilitates HIF-1α nuclear accumulation and chromatin engagement under hypoxia through a catalytic activity-independent, 14-3-3–regulated mechanism (PMID:39009674). AKT-mediated phosphorylation of USP43 drives its cytoplasmic retention via 14-3-3β/ε binding, creating a phosphorylation-dependent switch that governs nuclear versus cytoplasmic substrate access—a regulatory axis exploited in diabetic kidney disease, where high-glucose–induced AKT activity uncouples USP43 from the chaperone HSPA8 to promote SREBP-driven lipogenesis (PMID:30135474, PMID:40505547). Through stabilization of diverse substrates—including c-Myc, ZEB1, HDAC2, TAZ, RNF2, ASK1, TAK1, E2F1, and MYH9—USP43 influences cancer-related processes such as glycolysis, drug resistance, and metastasis, as well as non-cancer pathologies including ischemia–reperfusion injury and antiviral innate immune signaling (PMID:38218970, PMID:40148469, PMID:42012501).

1. 2018 High

   Establishing USP43 as an enzymatically active DUB with a defined nuclear function resolved what the gene product does: it associates with the NuRD complex, deubiquitinates H2BK120, and represses target genes including EGFR, linking a previously uncharacterized DUB to chromatin-level transcriptional regulation.

   Evidence Co-IP, in vitro DUB assay, ChIP, and loss/gain-of-function in breast cancer cells

   PMID:30135474

   Open questions at the time

   • Structural basis for NuRD complex association unknown
   • Full repertoire of USP43-repressed genes not defined
   • Whether catalytic activity versus scaffolding mediates NuRD recruitment not dissected
2. 2018 High

   Demonstrating that AKT phosphorylates USP43 to promote 14-3-3β/ε-mediated cytoplasmic sequestration established the first post-translational regulatory mechanism for this DUB, explaining how EGFR/PI3K/AKT signaling feeds back to limit USP43's nuclear tumor-suppressive activity.

   Evidence Phosphorylation assays, subcellular fractionation, Co-IP of 14-3-3, and live-cell imaging

   PMID:30135474

   Open questions at the time

   • Specific phosphorylation site(s) on USP43 not mapped
   • Whether other kinases also regulate USP43 localization unknown
   • Quantitative kinetics of shuttling not measured
3. 2021 Medium

   Identification of ZEB1 as a USP43 substrate in colorectal cancer extended USP43's role beyond chromatin modification to direct stabilization of an EMT-driving transcription factor, broadening its relevance to metastatic phenotypes.

   Evidence Co-IP, ubiquitination assay, knockdown/overexpression functional assays in CRC cells

   PMID:33391437

   Open questions at the time

   • Specific ubiquitination sites on ZEB1 not mapped
   • No in vivo validation of the USP43–ZEB1 axis
   • E3 ligase counterpart for ZEB1 in this context not identified
4. 2022 Medium

   Showing that USP43 stabilizes cortactin downstream of Cav2.2/NFAT2 signaling revealed a cytoplasmic, non-chromatin function for USP43 in invadopodia-mediated ECM degradation, demonstrating compartment-specific substrate selection.

   Evidence Co-IP, ubiquitination assay, invadopodia formation assay, and knockdown in breast cancer cells

   PMID:36137995

   Open questions at the time

   • Mechanism linking NFAT2 to USP43 upregulation not fully delineated
   • Whether 14-3-3 sequestration modulates the cortactin axis not tested
   • Single-lab finding
5. 2023 Medium

   Demonstration that USP43 stabilizes HDAC2 to activate Wnt/β-catenin signaling and reduce cisplatin sensitivity established USP43 as a modulator of drug resistance through epigenetic effector stabilization.

   Evidence Co-IP, ubiquitination assay, xenograft, Wnt reporter in epithelial ovarian cancer models

   PMID:38087046

   Open questions at the time

   • Ubiquitination sites on HDAC2 not mapped
   • Direct versus indirect effects on Wnt signaling not fully resolved
   • Single-lab finding
6. 2024 High

   Site-specific mapping of c-Myc deubiquitination at K148/K289 and demonstration of competition with FBXW7 provided the first residue-level substrate analysis for USP43 in a cancer-metabolic (glycolysis) context.

   Evidence siRNA library screen, Co-IP, site-directed mutagenesis, glycolysis/proliferation assays in bladder cancer

   PMID:38218970

   Open questions at the time

   • Whether USP43 directly competes with FBXW7 at the binding interface not structurally resolved
   • In vivo validation of glycolytic phenotype limited
7. 2024 High

   A genome-wide CRISPR DUB screen identified USP43 as essential for HIF-1α nuclear accumulation under hypoxia—without altering HIF-1α protein stability—revealing a catalytic-activity–independent, 14-3-3–regulated chaperone-like function distinct from canonical substrate deubiquitination.

   Evidence CRISPR/Cas9 sgRNA library screen, Co-IP, ChIP, nuclear fractionation, reporter assays

   PMID:39009674

   Open questions at the time

   • Catalytic-dead mutant rescue not shown for HIF-1α accumulation
   • Precise mechanism by which USP43 facilitates HIF-1α nuclear import unclear
   • Whether this non-canonical function extends to other transcription factors unknown
8. 2025 High

   Identification of RNF2 as a USP43 substrate via unbiased proteomics and ubiquitinomics, coupled with Usp43-knockout mouse studies, established USP43 as a negative regulator of type I interferon signaling through stabilization of the E3 ligase RNF2, which in turn degrades TBK1.

   Evidence Mass spectrometry interactome/ubiquitinome, site-directed mutagenesis (K239/K249), Usp43 KO mice with VSV infection

   PMID:40148469

   Open questions at the time

   • Whether the USP43–RNF2 axis operates in adaptive immunity not tested
   • Tissue-specific relevance beyond myeloid cells not explored
9. 2025 Medium

   Demonstrating that AKT-mediated phosphorylation of USP43 under high glucose disrupts the USP43–HSPA8 interaction, leading to HSPA8 degradation and SREBP-driven lipid accumulation, connected the established AKT/14-3-3 regulatory switch to metabolic disease (diabetic kidney disease).

   Evidence Co-IP, site-directed mutagenesis (HSPA8 K597R/K601R), phosphorylation assay, DKD mouse model

   PMID:40505547

   Open questions at the time

   • Precise phosphosite(s) on USP43 still not mapped
   • Whether HSPA8 stabilization is the primary protective mechanism in DKD not independently confirmed
   • Single-lab finding
10. 2025 Medium

    Parallel studies showed USP43 stabilizes ASK1 and TAK1 in cardiac and cerebral ischemia–reperfusion injury, respectively, activating JNK/p38 MAPK signaling and exacerbating tissue damage—expanding USP43 biology into acute sterile inflammation.

    Evidence Usp43 KO and cardiac-specific overexpression mice (I/R and MCAO models), Co-IP, ubiquitination assays, kinase inhibitor rescue

    PMID:41088415 PMID:42012501

    Open questions at the time

    • Whether ASK1 and TAK1 stabilization is cell-type autonomous not resolved
    • Therapeutic window for USP43 inhibition in I/R not defined
    • Findings from two independent labs but each axis validated by a single group
11. 2026 Medium

    Continued substrate discovery—E2F1, MYH9, ZBTB7A—linked USP43 to cholesterol biosynthesis–driven gemcitabine resistance, lenvatinib resistance via AKT/BAD, and VEGFA-mediated lymphangiogenesis, reinforcing USP43 as a pleiotropic K48-DUB with context-dependent oncogenic roles.

    Evidence Co-IP, ubiquitination assays, ChIP (ETS1), xenograft and lymphangiogenesis models across bladder and liver cancer

    PMID:41437393 PMID:41720328 PMID:41837877

    Open questions at the time

    • Substrate selectivity determinants remain uncharacterized at the structural level
    • No consensus motif or degron recognized by USP43 has been identified
    • Each substrate axis reported by a single lab

• The overarching open question is how USP43 achieves substrate selectivity across its numerous reported targets and whether its different functions (chromatin-level H2BK120 deubiquitination, catalytic-independent HIF-1α chaperoning, cytoplasmic substrate stabilization) reflect distinct regulatory states or complexes.
• No crystal or cryo-EM structure of USP43 exists
• No consensus substrate-recognition motif identified
• Relative physiological importance of individual substrates in vivo not ranked
• Phosphorylation site(s) mediating 14-3-3 binding remain unmapped