NUP98 (human, P52948) review notes

Provenance note: Provider deep research for NUP98 failed (Falcon returned HTTP 402
Payment Required; Perplexity not configured). No NUP98-deep-research-<provider>.md
file exists. The synthesis below replaces it and was written by the reviewing agent
from the UniProt record (NUP98-uniprot.txt) and the cached publications in
publications/. All quotes are verbatim from those sources.

Gene product and processing

• NUP98 encodes a precursor that is autoproteolytically cleaved. Isoforms 1/2 (the
  ~186-kDa Nup98-Nup96 precursor) yield two distinct nucleoporins, Nup98 (N-terminal,
  FG/GLFG-repeat containing) and Nup96 (C-terminal, a scaffold nucleoporin of the
  Nup107-160 "Y" complex); isoforms 3/4 (Nup98-specific) yield Nup98 only.
  PMID:10087256
  PMID:12191480
• GO annotations to P52948 therefore mix two biologically distinct proteins. Annotations
  concerning the Nup107-160 complex, the NPC outer ring, kinetochores in mitosis, and
  NPC scaffold assembly reflect Nup96; those concerning FG repeats, the permeability
  barrier, Rae1, mRNA export, intranuclear GLFG bodies, DHX9 and transcription reflect
  Nup98. No GOA rows in the current file carry an isoform identifier.

Nup98: FG-repeat permeability barrier and transport

• Nup98 is a GLFG/FG-repeat nucleoporin; its repeat domain provides docking sites for
  transport receptor-cargo complexes. PMID:7736573
• The intrinsically disordered Nup98 FG domain is the dominant component of the NPC
  selective permeability barrier (Xenopus), and Nup98 FG domains from diverse species,
  including human, phase-separate into particles with NPC-like permselectivity.
  PMID:25562883
  PMID:25562883
• UniProt: [file:human/NUP98/NUP98-uniprot.txt "NUP98 and NUP96 are involved in the bidirectional transport across the NPC"];
  [file:human/NUP98/NUP98-uniprot.txt "The FG repeat domains in Nup98 have a direct role in the transport."]
• mRNA export: Nup98 binds Rae1 via its GLEBS motif; the Rae1-Nup98 complex binds ssRNA.
  PMID:20498086
  PMID:20498086
  PMID:28221134
• Protein import/export: PMID:28221134.
  SARS-CoV-2 ORF6 binds Nup98-Rae1 and blocks STAT1/2 import, rescued by Nup98
  overexpression PMID:33097660.
  ORF6 also traps host mRNA in the nucleus PMID:33849972;
  VSV M protein targets Nup98 to block mRNA export (PMID:11106761).

Localization

• Nup98 is concentrated on the nucleoplasmic side of the NPC (nuclear basket region) and
  in the NPC core, with a mobile intranuclear pool that accumulates in GLFG bodies.
  PMID:7736573
  PMID:11839768
  PMID:15229283
  PMID:28221134
• Nup98 dissociates from NPCs early in prophase and re-assembles in anaphase/telophase
  (PMID:12802065).

Nup96: scaffold nucleoporin

• Nup96 is a stable member of the Nup107-160 complex (NPC outer rings), essential for NPC
  assembly, and with the complex localizes to kinetochores in mitosis.
  PMID:15229283
  PMID:15146057
  PMID:15146057

Off-pore gene regulation (Nup98)

• Intranuclear Nup98 binds chromatin/transcripts and acts as a cofactor of the helicase
  DHX9, stimulating its ATPase activity and supporting DHX9-dependent transcription and
  splicing. PMID:28221134
  PMID:28221134
• NUP98 N-terminal (FG-repeat) fusions to many partners (HOXA9, NSD1, KDM5A, PHF23 etc.)
  are recurrent drivers of AML and other leukemias (UniProt DISEASE notes).

Disease context (not in description)

• Alzheimer disease: in tangle-bearing neurons Nup98 is reported to mislocalize to the
  cytoplasm with tau, associated with nucleocytoplasmic transport failure (Eftekharzadeh
  et al. 2018, Neuron; not cached here, not cited in the review). This is a pathological
  state; normal Nup98 function is at the NPC and in the nucleoplasm. The core functions
  in the review (FG-repeat permeability barrier, structural constituent of nuclear pore,
  nucleocytoplasmic transport, mRNA export) are the normal functions that such a disease
  node would depend on.

Curation decisions summary

• Generic protein binding IPIs (Rae1, Nup107-160 members, viral ORF6, VSV M,
  interactome screens): REMOVE, except the DHX9 IPI (PMID:28221134), MODIFIED to
  ATPase activator activity (GO:0001671), which the paper directly supports.
• Reactome cytosol TAS rows: transport-reaction rows marked over-annotated (Nup98 is a
  pore component, not a cytosolic protein); mitosis-related rows (kinetochore, spindle,
  NPC reassembly) kept as non-core because after nuclear envelope breakdown the Nup96-
  containing Nup107-160 complex and dispersed Nup98 are cytoplasmic.
• protein carrier activity and peptide binding (IEA from rat Nup98): REMOVE — Nup98
  provides binding sites for transport receptors; it does not deliver cargo.
• nuclear inclusion body (aggregate foci): MODIFY to nuclear body (GLFG bodies).
• NEW: mRNA export from nucleus (GO:0006406); protein autoprocessing (GO:0016540; the
  C-terminal autoproteolytic domain cleaves its own precursor — the autoprocessing case
  explicitly allowed under proteolysis-type process terms).