NUP88

NUP88 is a cytoplasmic-face nuclear pore complex (NPC) component whose own incorporation into the pore depends on CAN/Nup214, with which it forms a constitutive subcomplex (PMID:9049309). Positioned midway between Nup358 and Nup214, NUP88 physically bridges these nucleoporins and is required to anchor Nup358 to the nuclear envelope, while NUP88 and Nup214 show mutual interdependence for their own NPC localization (PMID:14993277). The Nup214–NUP88 subcomplex provides a docking platform for CRM1-mediated nuclear export, being specifically required for export of the 60S preribosomal subunit via the NMD3 adaptor (PMID:9049309, PMID:16675447); this export function extends to regulatory cargoes, as NUP88/Nup214 promote nuclear export of the Notch effector RBP-J to restrain Notch target-gene expression (PMID:31186352) and contribute to nuclear retention of the osmoprotective transcription factor TonEBP under hypertonic stress (PMID:18606815). Beyond the cytoplasmic face, NUP88 also localizes to the nuclear side of the pore and binds the tail domain of lamin A through its N-terminus, an interaction disrupted by laminopathy-associated lamin A mutants (PMID:21289091). When overexpressed, NUP88 acquires oncogenic activity by sequestering the NUP98–RAE1 complex away from APC/C-CDH1, driving premitotic proteolysis of PLK1, spindle defects, aneuploidy, and tumor formation in mice (PMID:26731471), and it additionally promotes cancer-cell migration and invasion through MMP-12 upregulation (PMID:34331103). Biallelic loss-of-function mutations in NUP88 cause lethal fetal akinesia deformation sequence, mechanistically linked to reduced levels of rapsyn at the neuromuscular junction (PMID:30543681).

1. 1997 High

   Established NUP88 as a bona fide NPC component and defined the hierarchy of its assembly, answering how NUP88 is targeted to the pore.

   Evidence Co-IP, immunofluorescence, and depletion in CAN-/- mouse embryos showing CAN/Nup214-dependent NUP88 localization and a dynamic hCRM1-containing subcomplex

   PMID:9049309

   Open questions at the time

   • Did not resolve the structural basis of the Nup214–NUP88 interaction
   • Functional role of the CRM1 association not yet defined
2. 2004 High

   Defined NUP88's spatial position and connectivity on the cytoplasmic face, showing it bridges Nup214 and Nup358 and is required to anchor Nup358.

   Evidence RNAi knockdown with NE localization readout plus reciprocal co-IP in human cells

   PMID:14993277

   Open questions at the time

   • Stoichiometry of the Nup358–NUP88–Nup214 assembly not determined
   • Whether anchoring is direct or requires additional factors unresolved
3. 2006 High

   Assigned a specific transport function to the Nup214–NUP88 subcomplex, identifying it as the CRM1 platform for 60S preribosomal export rather than a general export factor.

   Evidence RNAi depletion with export assays and structure-function rescue using Nup214 deletion mutants

   PMID:16675447

   Open questions at the time

   • NUP88's own direct contribution versus that of Nup214 not separated
   • Generality across other ribosomal export cargoes not fully mapped
4. 2008 Medium

   Linked NUP88 to stress-responsive transcription by showing it retains TonEBP in the nucleus under hypertonic conditions, extending its export role to a regulatory transcription factor.

   Evidence Antibody microarray, RNAi knockdown, and GFP-TonEBP nuclear export reporter in IMCD3 cells

   PMID:18606815

   Open questions at the time

   • Mechanism of CRM1-independent TonEBP export under stress not defined
   • Direct NUP88–TonEBP interaction not shown
5. 2011 High

   Revealed a nuclear-face function for NUP88 by demonstrating a lamin A interaction with disease relevance, expanding its localization beyond the cytoplasmic face.

   Evidence In vitro binding, co-IP, epitope-masking IF, and IEM in Xenopus oocytes with laminopathy mutant testing

   PMID:21289091

   Open questions at the time

   • Functional consequence of the NUP88–lamin A interaction not established
   • Relationship to laminopathy pathology not tested in vivo
6. 2016 High

   Uncovered an oncogenic gain-of-function: overexpressed NUP88 sequesters NUP98-RAE1 from APC/C-CDH1 to trigger premitotic PLK1 degradation, aneuploidy, and tumors.

   Evidence Doxycycline-inducible transgenic mice, co-IP of the NUP88-NUP98-RAE1-APC/C axis, PLK1 proteolysis and mitosis imaging

   PMID:26731471

   Open questions at the time

   • Whether endogenous NUP88 levels modulate APC/C in normal cells unclear
   • Threshold of overexpression for the phenotype not quantified
7. 2016 Medium

   Connected NUP88 overexpression to a mitotic substrate by showing it interacts with MISP and blocks its PLK1-dependent phosphorylation.

   Evidence Proteomic interaction screen, co-IP, and phosphorylation assays

   PMID:27636375

   Open questions at the time

   • Direct versus PLK1-mediated effect on MISP phosphorylation not separated
   • Limited mechanistic follow-up beyond interaction
8. 2018 High

   Established NUP88 as a Mendelian disease gene, defining biallelic loss-of-function as the cause of fetal akinesia deformation sequence via reduced rapsyn at neuromuscular junctions.

   Evidence Human genetics, zebrafish nup88 knockout with wild-type vs mutant rescue, and rapsyn quantification in cell and fetal tissue

   PMID:30543681

   Open questions at the time

   • Mechanism linking NUP88 to rapsyn levels not defined
   • Whether the defect reflects transport or non-transport function unresolved
9. 2019 Medium

   Extended NUP88's export role to signaling control, showing NUP88/Nup214 export RBP-J to negatively regulate Notch target-gene expression.

   Evidence Reporter assays, ChIP-qPCR, immunocytochemistry, and in vivo zebrafish with Nup88/214 RNAi

   PMID:31186352

   Open questions at the time

   • Direct RBP-J–NUP88 contact not demonstrated
   • Dependence on CRM1 for RBP-J export not established
10. 2021 Medium

    Defined a pro-invasive activity of NUP88 distinct from its mitotic role, acting through MMP-12 upregulation rather than EMT or NF-κB.

    Evidence Gain- and loss-of-function in HeLa/cancer lines, invasion assays, MMP-12 quantification, and MMP-12 inhibitor rescue

    PMID:34331103

    Open questions at the time

    • Transcriptional mechanism of MMP-12 induction unknown
    • Relationship to the APC/C-PLK1 oncogenic pathway not addressed
11. 2023 Medium

    Identified Nup62 as a stabilizing partner that protects overexpressed NUP88 from proteasomal degradation, enabling NUP88-driven nuclear sequestration of NF-κB p65 and target-gene induction.

    Evidence Co-IP, proteasome inhibitor assays, and NF-κB target gene readouts with IF

    PMID:36845732

    Open questions at the time

    • Apparent tension with prior finding that NUP88 invasion is NF-κB-independent not reconciled
    • Single-lab characterization of the p65 mechanism

• How NUP88's distinct activities — cytoplasmic-face export scaffolding versus overexpression-driven mitotic and signaling oncogenicity — are mechanistically partitioned, and how loss-of-function specifically depletes rapsyn at neuromuscular junctions, remain open.
• No structural model of the Nup214–NUP88 subcomplex with CRM1
• Mechanism linking NUP88 loss to rapsyn reduction undefined
• Reconciliation of NF-κB-dependent and -independent oncogenic models needed