NUP88

NUP88 is a cytoplasmic-face nuclear pore complex (NPC) component that scaffolds NPC architecture, regulates selective nuclear export, and controls mitotic fidelity. Its NPC localization depends on CAN/NUP214, and together these nucleoporins mediate attachment of NUP358 to the pore and are specifically required for CRM1-dependent export of 60S preribosomal subunits (PMID:9049309, PMID:14993277, PMID:16675447). NUP88 directly binds lamin A via its N-terminus and modulates nuclear retention of transcription factors including NF-κB, TonEBP, and RBP-J, thereby influencing Notch signaling and osmotic stress responses (PMID:21289091, PMID:18606815, PMID:31186352, PMID:36845732). When overexpressed—a frequent event in tumors—NUP88 sequesters the NUP98–RAE1 complex away from APC/C-CDH1, causing premitotic PLK1 degradation, defective centrosome separation, and chromosomal instability (PMID:26731471).

1. 1997 High

   Identifying NUP88 as an NPC component whose pore localization depends on CAN/NUP214 established the first molecular dependency in the cytoplasmic nucleoporin network and linked NUP88 to the CRM1 export machinery.

   Evidence Co-immunoprecipitation and CAN depletion experiments in human cells

   PMID:9049309

   Open questions at the time

   • Stoichiometry of the NUP88–NUP214–CRM1 subcomplex unknown
   • Whether NUP88 contacts CRM1 directly or only via NUP214 unresolved
2. 2004 High

   Demonstrating that NUP88 and NUP214 are both required for NUP358 attachment to the NPC revealed NUP88 as a structural scaffold of the cytoplasmic filament network, resolving how the outermost pore components are anchored.

   Evidence RNAi of NUP88/NUP214 with immunofluorescence and electron microscopy readouts

   PMID:14993277

   Open questions at the time

   • Direct binding interface between NUP88 and NUP358 not mapped
   • Whether NUP88 loss affects NPC transport beyond NUP358-dependent pathways unclear
3. 2006 High

   Showing that the NUP214–NUP88 subcomplex is specifically required for CRM1-mediated 60S preribosomal export—but largely dispensable for other CRM1 cargoes—revealed cargo selectivity at individual NPC subcomplexes.

   Evidence RNAi depletion coupled with specific nuclear export assays and NUP214 domain rescue constructs

   PMID:16675447

   Open questions at the time

   • How NUP88 itself contributes to 60S selectivity versus serving only as a NUP214 anchor unresolved
   • Other potential cargo-specific export roles of NUP88 not surveyed
4. 2008 Medium

   Finding that NUP88 upregulation under hypertonic stress retains TonEBP in the nucleus provided the first evidence that NUP88 levels modulate transcription factor localization in a physiological signaling context.

   Evidence siRNA knockdown in kidney IMCD3 cells with GFP-TonEBP nuclear retention assays and CRM1 inhibitor treatment

   PMID:18606815

   Open questions at the time

   • Mechanism by which NUP88 retains TonEBP independently of CRM1 not defined
   • Whether NUP88 directly contacts TonEBP or acts indirectly unknown
5. 2011 High

   Demonstrating direct NUP88–lamin A binding and showing disruption by laminopathy mutations expanded NUP88 function beyond the cytoplasmic face to a structural link between the NPC and the nuclear lamina.

   Evidence In vitro binding assays, co-immunoprecipitation, immunoelectron microscopy in Xenopus oocytes

   PMID:21289091

   Open questions at the time

   • Functional consequence of NUP88–lamin A disruption on NPC integrity or transport not established
   • Whether loss of this interaction contributes to laminopathy phenotypes untested in vivo
6. 2016 High

   Elucidating the NUP88→NUP98-RAE1→APC/C-CDH1→PLK1 axis explained how NUP88 overexpression causes chromosomal instability, providing a mechanistic link between nucleoporin dysregulation and aneuploidy in cancer.

   Evidence Transgenic NUP88-overexpressing mice, co-immunoprecipitation, live-cell imaging, PLK1 rescue experiments

   PMID:26731471

   Open questions at the time

   • Whether endogenous NUP88 levels regulate PLK1 during normal mitosis unknown
   • Tissue-specific thresholds for NUP88 overexpression to induce CIN not determined
7. 2018 Medium

   Linking NUP88 loss of function to neuromuscular junction defects via rapsyn dysregulation in zebrafish and mammalian cells expanded the gene's physiological roles to tissue-specific developmental processes.

   Evidence siRNA in human/mouse cells, zebrafish mutant analysis with wild-type vs. mutant rescue

   PMID:30543681

   Open questions at the time

   • Whether NUP88 directly interacts with rapsyn or acts via nuclear transport of an upstream regulator unresolved
   • Specific NUP88 mutations found in patients not functionally characterized at the NPC level
8. 2019 Medium

   Showing that NUP88/NUP214 loss inhibits nuclear export of RBP-J, thereby amplifying Notch signaling, revealed NUP88 as a negative regulator of a major developmental signaling pathway.

   Evidence Reporter assays, ChIP-qPCR, RNAi in mammalian cells, zebrafish validation

   PMID:31186352

   Open questions at the time

   • Whether RBP-J export is CRM1-dependent through NUP88 or uses an alternative pathway not resolved
   • Physiological contexts where NUP88-mediated Notch regulation is rate-limiting unknown
9. 2023 Medium

   Identifying NUP62 as a stabilizer of overexpressed NUP88 (by blocking proteasomal degradation) and showing that stabilized NUP88 sequesters NF-κB p65 in the nucleus clarified how NUP88 overexpression in tumors could constitutively activate NF-κB target genes.

   Evidence Co-immunoprecipitation, proteasome inhibitor assays, gene expression analysis in human cells

   PMID:36845732

   Open questions at the time

   • Whether NUP88–p65 interaction is direct not determined
   • In vivo relevance of NUP62-dependent NUP88 stabilization in tumors not tested

• A unifying structural model of how NUP88 simultaneously scaffolds NUP214, NUP358, and lamin A at the NPC, and how its stoichiometric balance controls the switch between transport and mitotic regulation, remains unresolved.
• No high-resolution structure of NUP88 in the context of the intact NPC subcomplex
• Mechanism by which NUP88 selectively modulates export of specific transcription factors versus bulk CRM1 cargo unknown
• Whether NUP88 overexpression-driven CIN and NF-κB activation operate through independent or convergent oncogenic pathways not determined