NUP85

NUP85 is a nuclear pore complex (NPC) component required for normal NPC abundance and mitotic fidelity, and it additionally functions in hepatic lipid and fibrotic signaling (PMID:34170319, PMID:41903125). Biallelic loss-of-function variants reduce the number of assembled NPCs without disrupting nucleocytoplasmic compartmentalization, while producing abnormal mitotic spindle morphology and decreased cell viability and proliferation in patient-derived fibroblasts, establishing a role in NPC number control and mitotic spindle integrity (PMID:34170319). In the liver, NUP85 acts as a driver of lipid accumulation and inflammation: it interacts with the chemokine receptor CCR2 to sustain PI3K/AKT phosphorylation, and modulates the SLC27A1/PPAR-γ axis to upregulate lipid-synthesis and inflammatory genes, such that NUP85 knockdown alleviates hepatic steatosis (PMID:38617542, PMID:41413582). NUP85 also promotes liver fibrosis by competitively binding USP47 away from ASK1, blocking deubiquitination of ASK1 at K805 and thereby activating ASK1-driven endoplasmic reticulum stress and collagen deposition (PMID:41903125). In Drosophila testes, the ortholog Nup75 controls early germ-cell proliferation and maintains hub-cell quiescence, with lineage-specific depletion causing germline loss (PMID:37286104).

1. 2021 Medium

   Established that NUP85 controls NPC abundance and mitotic spindle integrity rather than acting primarily through bulk nucleocytoplasmic transport, reframing how its loss causes disease.

   Evidence Patient-derived fibroblast immunofluorescence for NPC number, transport assays, spindle imaging, and viability/proliferation assays

   PMID:34170319

   Open questions at the time

   • No reconstitution or in vitro biochemistry defining NUP85's structural role in the Y-complex
   • Mechanism linking reduced NPC number to spindle defects unresolved
2. 2023 Low

   Tested whether additional NUP85 missense variants impair function, linking patient genotypes to reduced viability and predicted disruption of neighboring nucleoporin contacts.

   Evidence Patient-derived fibroblast viability assay with computational structural modeling of variants

   PMID:36846113

   Open questions at the time

   • Cell viability is a single assay with no pathway placement
   • Structural prediction is computational only without experimental validation
   • Single case report
3. 2023 Medium

   Extended NUP85 function to tissue-specific stem cell regulation by showing the Drosophila ortholog governs early germ-cell proliferation and hub-cell quiescence.

   Evidence Lineage-specific RNAi knockdown in Drosophila testis with cell-fate marker immunofluorescence

   PMID:37286104

   Open questions at the time

   • No mammalian validation of the germline role
   • Molecular pathway connecting Nup75 to proliferation control not defined
4. 2024 Medium

   Identified a non-NPC signaling role: NUP85 interacts with CCR2 and sustains PI3K/AKT signaling to promote hepatic lipid accumulation and inflammation.

   Evidence Co-immunoprecipitation, siRNA knockdown in AML-12 cells and MCD-diet mouse model with signaling readouts

   PMID:38617542

   Open questions at the time

   • Single lab with limited orthogonal validation
   • Direct vs indirect nature of CCR2 interaction not fully resolved
   • How a nucleoporin engages a chemokine receptor mechanistically unclear
5. 2025 Medium

   Defined a second hepatic lipid mechanism through the SLC27A1/PPAR-γ axis, showing in vivo knockdown relieves steatosis and inflammation.

   Evidence siRNA knockdown in hepatocytes and HFD/MCD mouse models with SLC27A1/PPAR-γ expression analysis

   PMID:41413582

   Open questions at the time

   • No direct binding evidence for the SLC27A1 link
   • Relationship between this axis and the CCR2/PI3K-AKT axis unresolved
6. 2026 Medium

   Mechanistically connected NUP85 to liver fibrosis via competitive binding to USP47, blocking ASK1 deubiquitination at K805 to activate ER stress and collagen deposition.

   Evidence Co-IP for NUP85-USP47 and NUP85-ASK1, site-specific mutagenesis of ASK1 K805, knockdown/overexpression with ERS and fibrosis readouts in cells and mice

   PMID:41903125

   Open questions at the time

   • Single lab without orthogonal structural validation of the competitive binding model
   • How NUP85's nuclear pore role relates to cytoplasmic USP47/ASK1 regulation unclear

• It remains unresolved how NUP85's structural role at the nuclear pore mechanistically connects to its diverse cytoplasmic signaling functions in liver lipid metabolism and fibrosis.
• No structural or biochemical reconstitution of NUP85 within the Y-complex in the corpus
• No unifying model linking NPC function to CCR2, SLC27A1/PPAR-γ, and USP47/ASK1 signaling