NUP85

NUP85 is a structural nucleoporin that functions as a core subunit of the Nup107-160 subcomplex, contributing to the scaffold architecture of the nuclear pore complex and relocalizing to kinetochores during mitosis to support chromosome segregation. Proteomic analysis of purified NPCs identified NUP85 as one of ~29 nucleoporins (PMID:12196509), and integrated cryo-electron tomography established that 32 copies of the Nup107-160 subcomplex—including NUP85—assemble into two reticulated rings at the cytoplasmic and nuclear faces of the NPC, with NUP85 directly contacting Nup43 (PMID:24315095, PMID:24927568). Biallelic loss-of-function NUP85 variants reduce NPC number and cause abnormal mitotic spindle morphology, linking NUP85 to primary microcephaly and Seckel syndrome (PMID:34170319). Beyond its canonical NPC role, NUP85 modulates hepatic lipid metabolism through the SLC27A1/PPAR-γ axis and promotes liver fibrosis by competitively displacing USP47 from ASK1, preventing deubiquitination at K805 and thereby activating ASK1-dependent collagen deposition (PMID:41413582, PMID:41903125).

1. 2002 High

   Establishing NUP85 as a bona fide nucleoporin resolved its identity as one of the ~29 proteins constituting the mammalian nuclear pore complex, providing the foundation for all subsequent functional studies.

   Evidence Biochemical purification of NPCs followed by mass spectrometry and subcellular localization in HeLa cells

   PMID:12196509

   Open questions at the time

   • Subcomplex membership and direct binding partners were not defined
   • No functional data on NUP85 depletion phenotype
2. 2004 High

   Demonstrating that NUP85 is a core member of the Nup107-160 subcomplex and that this entire complex relocalizes to kinetochores during mitosis established a dual role for NUP85 in both interphase nuclear transport and mitotic chromosome segregation.

   Evidence GFP-tagged nucleoporin live imaging, immunofluorescence, and RNAi knockdown in mammalian cells

   PMID:15146057

   Open questions at the time

   • Precise position of NUP85 within the Nup107-160 complex was unknown
   • Mechanism by which NUP85 contributes to kinetochore function was not defined
3. 2013 High

   Defining the stoichiometry and spatial arrangement of the Nup107-160 subcomplex within the intact NPC—32 copies forming two reticulated rings—positioned NUP85 within the three-dimensional NPC scaffold and explained how multiple copies contribute to NPC integrity.

   Evidence Cryo-electron tomography, single-particle EM, and crosslinking mass spectrometry of human NPCs

   PMID:24315095

   Open questions at the time

   • Atomic-resolution contacts between NUP85 and its immediate neighbors were not resolved
   • Functional consequence of disrupting NUP85's specific ring position was untested
4. 2014 High

   BioID proximity labeling identified Nup43 as a direct in vivo neighbor of NUP85 within the NPC, establishing a specific molecular contact within the Nup107-160 subcomplex.

   Evidence BioID proximity-dependent biotinylation and mass spectrometry in living cells

   PMID:24927568

   Open questions at the time

   • Whether Nup43 binding is required for NUP85 incorporation into the NPC was not tested
   • Full interaction surface and stoichiometry of the NUP85–Nup43 contact remain unresolved
5. 2021 Medium

   Linking biallelic NUP85 loss-of-function variants to reduced NPC number, abnormal mitotic spindles, and primary microcephaly/Seckel syndrome established NUP85 as essential for nervous system development and demonstrated that its structural role has direct clinical consequences.

   Evidence Patient-derived fibroblast analysis with immunofluorescence for NPC number, mitotic spindle morphology, and cell viability assays

   PMID:34170319

   Open questions at the time

   • Mechanism by which reduced NPC number leads to microcephaly is not defined
   • No rescue experiment restoring NUP85 expression in patient cells was reported
   • Bulk nucleocytoplasmic transport was unaffected, leaving the critical cargo or signaling deficit unknown
6. 2024 Medium

   Identifying a physical interaction between NUP85 and CCR2 in hepatocytes, with NUP85 knockdown reducing CCR2 levels and PI3K/AKT signaling, revealed an NPC-independent role for NUP85 in hepatic lipid metabolism and inflammation.

   Evidence Co-immunoprecipitation and siRNA knockdown in AML-12 cells and MCD-diet mouse model with Western blot and lipid accumulation assays

   PMID:38617542

   Open questions at the time

   • NUP85–CCR2 interaction lacks reciprocal validation or structural evidence
   • Whether this function requires NUP85 at the NPC or involves a soluble pool is unknown
   • Single-lab finding not independently replicated
7. 2025 Medium

   Demonstrating that NUP85 promotes hepatic lipid accumulation through the SLC27A1/PPAR-γ axis defined a specific transcriptional and metabolic pathway downstream of NUP85 in lipotoxic hepatocytes.

   Evidence siRNA knockdown in vitro and in vivo (HFD/MCD mouse models) delivered via RBC-derived extracellular vesicles, with gene expression and lipid accumulation readouts

   PMID:41413582

   Open questions at the time

   • Whether NUP85 directly regulates SLC27A1 transcription or acts indirectly is not resolved
   • Relationship between NPC structural role and metabolic function is unclear
   • Single-lab finding not independently replicated
8. 2026 Medium

   Showing that NUP85 competitively displaces USP47 from ASK1 to prevent deubiquitination at K805, thereby promoting ASK1 activation and liver fibrosis, established a precise non-NPC mechanism through which NUP85 modulates ubiquitin signaling.

   Evidence Co-immunoprecipitation, competitive binding assays, site-specific ubiquitination analysis at ASK1 K805, knockdown and overexpression in liver fibrosis mouse models and cell lines

   PMID:41903125

   Open questions at the time

   • Whether the NUP85–USP47 interaction occurs at the NPC or in the soluble pool is unknown
   • Structural basis for competitive displacement has not been determined
   • Single-lab finding; independent replication needed

• It remains unknown how NUP85's canonical NPC scaffold role and its emerging non-NPC functions in hepatic lipid metabolism and fibrosis are coordinated, and whether a soluble or NPC-associated pool of NUP85 mediates these distinct activities.
• No study has determined whether NUP85 exists in functionally distinct pools
• Atomic-resolution structure of NUP85 in complex with its NPC neighbors is lacking
• Mechanism linking reduced NPC number to microcephaly is undefined