NUP98 Protein
<div class="infobox infobox-protein">
<table>
<tr><th>Protein</th><td>Nucleoporin 98 (NUP98)</td></tr>
<tr><th>Encoded by</th><td>[NUP98](/genes/nup98)</td></tr>
<tr><th>UniProt</th><td>[P52948](https://www.uniprot.org/uniprot/P52948)</td></tr>
<tr><th>Molecular weight</th><td>~98 kDa (precursor); ~98 kDa NUP98, ~96 kDa NUP96 after autoproteolysis</td></tr>
<tr><th>Subcellular localization</th><td>Nuclear pore complex, nucleoplasm</td></tr>
<tr><th>Protein family</th><td>GLFG-nucleoporin family</td></tr>
<tr><th>Key disease links</th><td>[ALS](/diseases/als), [FTD](/diseases/ftd), [Alzheimer's disease](/diseases/alzheimers-disease)</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/neurodegeneration" style="color:#ef9a9a">Neurodegeneration</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">10 edges</a></td>
</tr>
</table>
</div>
Overview
NUP98 is a GLFG-repeat nucleoporin that plays dual roles in nucleocytoplasmic transport and transcriptional regulation.[@fontoura1999][@griffis2004] Unlike most NPC components, NUP98 is dynamically associated with the nuclear pore and shuttles between the NPC and nucleoplasmic gene loci, where it acts as a transcriptional activator at developmental and neuronal activity-responsive genes.[@kalverda2010][@light2010] Dysfunction of NUP98 has emerged as a convergent pathological mechanism in [ALS](/diseases/als), [FTD](/diseases/ftd), and [Alzheimer's disease](/diseases/alzheimers-disease), driven by its susceptibility to disruption by dipeptide repeat proteins and [tau](/proteins/tau) aggregates.[@freibaum2015][@eftekharzadeh2018]
Structure
The NUP98 precursor undergoes autoproteolytic cleavage to generate two proteins: NUP98 (N-terminal, containing the GLFG-repeat domain) and NUP96 (C-terminal, a structural scaffold nucleoporin).[@fontoura1999] The NUP98 moiety contains approximately 40 GLFG repeats within an intrinsically disordered ~500-residue N-terminal domain that mediates both NPC permeability barrier function and liquid-liquid phase separation (LLPS).[@schmidt2015] A Gle2-binding sequence (GLEBS) motif mediates mRNA export through interaction with the Rae1/Gle2 export factor.[@blevins2003] The C-terminal autoproteolytic domain contains a conserved HFS (His-Phe-Ser) catalytic triad.[@fontoura1999]
Normal Function
NUP98 performs several critical functions in [neurons](/entities/neurons):
- Selective transport barrier: The GLFG-repeat domain contributes to the NPC central channel hydrogel, creating selective permeability for nuclear transport receptors while excluding large inert macromolecules.[@schmidt2015][@hlsmann2012]
- mRNA export: Through its GLEBS motif interaction with Rae1, NUP98 facilitates export of mature mRNAs, with particular importance for activity-dependent transcripts in neurons.[@blevins2003]
- Transcriptional memory: NUP98 marks recently active genes through association with promoter and enhancer regions, maintaining epigenetic memory of transcriptional states — a function critical for synaptic plasticity-related gene programs.[@kalverda2010][@light2010]
- Phase separation scaffold: NUP98 GLFG repeats can phase-separate to form hydrogel-like condensates that reconstitute NPC selectivity in vitro and may nucleate transport-competent assemblies during NPC biogenesis.[@schmidt2015]
Role in Neurodegeneration
ALS/FTD
NUP98 is a primary target of [C9orf72](/genes/c9orf72) dipeptide repeat protein toxicity. Poly-PR and poly-GR arginine-rich DPRs directly interact with NUP98 GLFG-repeat domains, dissolving the phase-separated transport barrier and causing catastrophic loss of NPC selectivity.[@freibaum2015][@zhang2015] This disruption leads to nuclear depletion of essential RNA-binding proteins including [TDP-43](/proteins/tdp-43) and [FUS](/proteins/fus-protein), while cytoplasmic proteins gain aberrant nuclear access.[@kim2017] In Drosophila models, NUP98 overexpression partially rescues [C9orf72](/entities/c9orf72) DPR toxicity, establishing NUP98 depletion as a rate-limiting step in neurodegeneration.[@freibaum2015]
Alzheimer's Disease
Hyperphosphorylated [tau](/proteins/tau) disrupts NUP98 localization and function through direct binding to the GLFG-repeat domain.[@eftekharzadeh2018] In human AD brain tissue, NUP98 is mislocalized from the nuclear envelope to cytoplasmic tau inclusions, correlating with impaired nuclear import of neuroprotective transcription factors (CREB, NF-κB).[@sheffield2006] The tau-NUP98 interaction is phosphorylation-dependent, with AT8-positive tau species showing highest affinity, suggesting that early tau pathology may initiate transport deficits before frank tangle formation.[@eftekharzadeh2018]
Aging
NUP98, like [NUP62](/proteins/nup62-protein), is among the longest-lived proteins in postmitotic neurons. Oxidative carbonylation of GLFG repeats accumulates over decades, progressively reducing phase separation capacity and transport fidelity.[@dangelo2009][@toyama2013] This age-dependent NPC deterioration may establish a permissive environment for protein mislocalization that predisposes to neurodegeneration.
Therapeutic Targeting
- Phase separation stabilizers: Small molecules that enhance NUP98 GLFG-repeat cohesion, potentially counteracting DPR-mediated disruption of NPC hydrogels.[@schmidt2015]
- Nuclear import restoration: Compounds enhancing importin-β mediated transport (e.g., through Ran-GTPase gradient stabilization) to compensate for partial NUP98 loss-of-function.[@gassetrosa2017]
- DPR-targeted approaches: ASOs and small molecules that reduce C9orf72 repeat RNA and DPR production, preventing upstream NUP98 dysfunction.[@zhang2015]
- Proteasome/autophagy modulation: Enhancing clearance of oxidatively damaged NUP98 to promote turnover and replacement with functional copies.[@toyama2013]
See Also
- [NUP98](/genes/nup98)
- [NUP62 Protein](/proteins/nup62-protein)
- [C9orf72](/genes/c9orf72)
- [TDP-43](/proteins/tdp-43)
- [Nucleocytoplasmic Transport Defects](/mechanisms/nucleocytoplasmic-transport-defects)
External Links
- [UniProt: nup98](https://www.uniprot.org/)
- [PubMed: nup98](https://pubmed.ncbi.nlm.nih.gov/?term=nup98+neurodegeneration)## Cross-Links to Related Pages
Diseases
- [Amyotrophic Lateral Sclerosis (ALS)](/diseases/amyotrophic-lateral-sclerosis)
- [Frontotemporal Dementia (FTD)](/diseases/frontotemporal-dementia)
- [Parkinson's Disease](/diseases/parkinsons-disease)
Genes & Proteins
- [C9orf72](/entities/c9orf72)
- [TDP-43](/biomarkers/tdp-43)
- [FUS](/entities/fus-protein)
- [SOD1](/entities/sod1)
- RAN Translation Proteins
Mechanisms
- RNA Targeting
- Dipeptide Repeat Toxicity
- [Nucleocytoplasmic Transport Defects](/mechanisms/nucleocytoplasmic-transport-defects)
- Stress Granule Dysfunction
- [RNA Metabolism](/mechanisms/rna-metabolism)
- Hexanucleotide Repeat Expansion
Cell Types
- [Motor Neurons](/cell-types/motor-neurons)
- [Neurons](/cell-types/neurons)
- [Astrocytes](/cell-types/astrocytes)
- [Microglia](/cell-types/microglia)
Treatments
- ASO Therapy
- RNAi Therapy
- [Gene Therapy](/technologies/gene-therapy)
- [Antisense Oligonucleotides](/therapeutics/antisense-oligonucleotides)
- TDP43 Molecular Glue
- Splice Modulation Therapy
Overview
NUP98 is a GLFG-repeat nucleoporin that plays dual roles in nucleocytoplasmic transport and transcriptional regulation.[@fontoura1999][@griffis2004] Unlike most NPC components, NUP98 is dynamically associated with the nuclear pore and shuttles between the NPC and nucleoplasmic gene loci, where it acts as a transcriptional activator at developmental and neuronal activity-responsive genes.[@kalverda2010][@light2010] Dysfunction of NUP98 has emerged as a convergent pathological mechanism in ALS, FTD, and Alzheimer's disease, driven by its susceptibility to disruption by dipeptide repeat proteins and tau aggregates.[@freibaum2015][@eftekharzadeh2018]
Structure
The NUP98 precursor undergoes autoproteolytic cleavage to generate two proteins: NUP98 (N-terminal, containing the GLFG-repeat domain) and NUP96 (C-terminal, a structural scaffold nucleoporin).[@fontoura1999] The NUP98 moiety contains approximately 40 GLFG repeats within an intrinsically disordered ~500-residue N-terminal domain that mediates both NPC permeability barrier function and liquid-liquid phase separation (LLPS).[@schmidt2015] A Gle2-binding sequence (GLEBS) motif mediates mRNA export through interaction with the Rae1/Gle2 export factor.[@blevins2003] The C-terminal autoproteolytic domain contains a conserved HFS (His-Phe-Ser) catalytic triad.[@fontoura1999]
Normal Function
NUP98 performs several critical functions in neurons:
- Selective transport barrier: The GLFG-repeat domain contributes to the NPC central channel hydrogel, creating selective permeability for nuclear transport receptors while excluding large inert macromolecules.[@schmidt2015][@hlsmann2012]
- mRNA export: Through its GLEBS motif interaction with Rae1, NUP98 facilitates export of mature mRNAs, with particular importance for activity-dependent transcripts in neurons.[@blevins2003]
- Transcriptional memory: NUP98 marks recently active genes through association with promoter and enhancer regions, maintaining epigenetic memory of transcriptional states — a function critical for synaptic plasticity-related gene programs.[@kalverda2010][@light2010]
- Phase separation scaffold: NUP98 GLFG repeats can phase-separate to form hydrogel-like condensates that reconstitute NPC selectivity in vitro and may nucleate transport-competent assemblies during NPC biogenesis.[@schmidt2015]
Role in Neurodegeneration
ALS/FTD
NUP98 is a primary target of C9orf72 dipeptide repeat protein toxicity. Poly-PR and poly-GR arginine-rich DPRs directly interact with NUP98 GLFG-repeat domains, dissolving the phase-separated transport barrier and causing catastrophic loss of NPC selectivity.[@freibaum2015][@zhang2015] This disruption leads to nuclear depletion of essential RNA-binding proteins including TDP-43 and FUS, while cytoplasmic proteins gain aberrant nuclear access.[@kim2017] In Drosophila models, NUP98 overexpression partially rescues C9orf72 DPR toxicity, establishing NUP98 depletion as a rate-limiting step in neurodegeneration.[@freibaum2015]
Alzheimer's Disease
Hyperphosphorylated tau disrupts NUP98 localization and function through direct binding to the GLFG-repeat domain.[@eftekharzadeh2018] In human AD brain tissue, NUP98 is mislocalized from the nuclear envelope to cytoplasmic tau inclusions, correlating with impaired nuclear import of neuroprotective transcription factors (CREB, NF-κB).[@sheffield2006] The tau-NUP98 interaction is phosphorylation-dependent, with AT8-positive tau species showing highest affinity, suggesting that early tau pathology may initiate transport deficits before frank tangle formation.[@eftekharzadeh2018]
Aging
NUP98, like NUP62, is among the longest-lived proteins in postmitotic neurons. Oxidative carbonylation of GLFG repeats accumulates over decades, progressively reducing phase separation capacity and transport fidelity.[@dangelo2009][@toyama2013] This age-dependent NPC deterioration may establish a permissive environment for protein mislocalization that predisposes to neurodegeneration.
Therapeutic Targeting
- Phase separation stabilizers: Small molecules that enhance NUP98 GLFG-repeat cohesion, potentially counteracting DPR-mediated disruption of NPC hydrogels.[@schmidt2015]
- Nuclear import restoration: Compounds enhancing importin-β mediated transport (e.g., through Ran-GTPase gradient stabilization) to compensate for partial NUP98 loss-of-function.[@gassetrosa2017]
- DPR-targeted approaches: ASOs and small molecules that reduce C9orf72 repeat RNA and DPR production, preventing upstream NUP98 dysfunction.[@zhang2015]
- Proteasome/autophagy modulation: Enhancing clearance of oxidatively damaged NUP98 to promote turnover and replacement with functional copies.[@toyama2013]
See Also
- NUP98
- NUP62 Protein
- C9orf72
- TDP-43
- Nucleocytoplasmic Transport Defects
References
- [UniProt: nup98](https://www.uniprot.org/)
- [PubMed: nup98](https://pubme