| Protein | Nucleoporin 98 (NUP98) |
|---|---|
| Encoded by | [NUP98](/genes/nup98) |
| UniProt | [P52948](https://www.uniprot.org/uniprot/P52948) |
| Molecular weight | ~98 kDa (precursor); ~98 kDa NUP98, ~96 kDa NUP96 after autoproteolysis |
| Subcellular localization | Nuclear pore complex, nucleoplasm |
| Protein family | GLFG-nucleoporin family |
| Key disease links | [ALS](/diseases/als), [FTD](/diseases/ftd), [Alzheimer's disease](/diseases/alzheimers-disease) |
NUP98 is a GLFG-repeat nucleoporin that plays dual roles in nucleocytoplasmic transport and transcriptional regulation.[1][2] 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.[3][4] 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.[5][6]
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).[1:1] 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).[7] A Gle2-binding sequence (GLEBS) motif mediates mRNA export through interaction with the Rae1/Gle2 export factor.[8] The C-terminal autoproteolytic domain contains a conserved HFS (His-Phe-Ser) catalytic triad.[1:2]
NUP98 performs several critical functions in neurons:
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.[5:1][10] This disruption leads to nuclear depletion of essential RNA-binding proteins including TDP-43 and FUS, while cytoplasmic proteins gain aberrant nuclear access.[11] In Drosophila models, NUP98 overexpression partially rescues C9orf72 DPR toxicity, establishing NUP98 depletion as a rate-limiting step in neurodegeneration.[5:2]
Hyperphosphorylated tau disrupts NUP98 localization and function through direct binding to the GLFG-repeat domain.[6:1] 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).[12] 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.[6:2]
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.[13][14] This age-dependent NPC deterioration may establish a permissive environment for protein mislocalization that predisposes to neurodegeneration.
NUP98 is a GLFG-repeat nucleoporin that plays dual roles in nucleocytoplasmic transport and transcriptional regulation.[1:3][2:1] 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.[3:2][4:2] 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.[5:3][6:3]
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).[1:4] 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).[7:4] A Gle2-binding sequence (GLEBS) motif mediates mRNA export through interaction with the Rae1/Gle2 export factor.[8:2] The C-terminal autoproteolytic domain contains a conserved HFS (His-Phe-Ser) catalytic triad.[1:5]
NUP98 performs several critical functions in neurons:
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.[5:4][10:2] This disruption leads to nuclear depletion of essential RNA-binding proteins including TDP-43 and FUS, while cytoplasmic proteins gain aberrant nuclear access.[11:1] In Drosophila models, NUP98 overexpression partially rescues C9orf72 DPR toxicity, establishing NUP98 depletion as a rate-limiting step in neurodegeneration.[5:5]
Hyperphosphorylated tau disrupts NUP98 localization and function through direct binding to the GLFG-repeat domain.[6:4] 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).[12:1] 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.[6:5]
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.[13:1][14:2] This age-dependent NPC deterioration may establish a permissive environment for protein mislocalization that predisposes to neurodegeneration.
Fontoura BM, Blobel G, Matunis MJ. A conserved biogenesis pathway for nucleoporins: proteolytic processing of a 186-kilodalton precursor generates Nup98 and the novel nucleoporin, Nup96. J Cell Biol. 1999. ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎
Griffis ER, Alber F, Bhatt DL, et al. Nup98 is a mobile nucleoporin with transcription-dependent dynamics. Mol Biol Cell. 2004. ↩︎ ↩︎
Kalverda B, Pickersgill H, Shloma VV, Fornerod M. Nucleoporins directly stimulate expression of developmental and cell-cycle genes inside the nucleoplasm. Cell. 2010. ↩︎ ↩︎ ↩︎ ↩︎
Light WH, Brickner DG, Brand VR, Brickner JH. Interaction of a DNA zip code with the nuclear pore complex promotes H2A.Z incorporation and INO1 transcriptional memory. Mol Cell. 2010. ↩︎ ↩︎ ↩︎ ↩︎
Freibaum BD, Lu Y, Lopez-Gonzalez R, et al. GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature. 2015. ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎
Eftekharzadeh B, Daiber JA, Nober W, et al. Tau protein disrupts nucleocytoplasmic transport in Alzheimer's disease. Neuron. 2018. ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎
Schmidt HB, Görlich D. Nup98 FG domains from diverse species spontaneously phase-separate into particles with nuclear pore-like permselectivity. eLife. 2015. ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎
Blevins MB, Smith AM, Phillips EM, Powers MA. Complex formation among the RNA export proteins Nup98, Rae1/Gle2, and TAP. J Biol Chem. 2003. ↩︎ ↩︎ ↩︎ ↩︎
Hülsmann BB, Labokha AA, Görlich D. The permeability of reconstituted nuclear pores provides direct evidence for the selective phase model. Cell. 2012. ↩︎ ↩︎
Zhang K, Donnelly CJ, Haeusler AR, et al. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature. 2015. ↩︎ ↩︎ ↩︎ ↩︎
Kim HJ, Taylor JP. Lost in transportation: nucleocytoplasmic transport deficits in ALS and other neurodegenerative diseases. Neuron. 2017. ↩︎ ↩︎
Sheffield LG, Miskiewicz HB, Tannenbaum LB, Bhatt DL. Nuclear pore complex proteins in Alzheimer disease. J Neuroimmune Pharmacol. 2006. ↩︎ ↩︎
D'Angelo MA, Raices M, Bhatt DL, et al. Age-dependent deterioration of nuclear pore complexes causes a loss of nuclear integrity in postmitotic cells. Cell. 2009. ↩︎ ↩︎
Toyama BH, Savas JN, Park SK, et al. Identification of long-lived proteins reveals exceptional stability of histones and nuclear pore complexes. Cell. 2013. ↩︎ ↩︎ ↩︎ ↩︎
Gasset-Rosa F, Chillon-Marinas C, Goginashvili A, et al. Polyglutamine-expanded huntingtin exacerbates age-related disruption of nuclear integrity and nucleocytoplasmic transport. Neuron. 2017. ↩︎ ↩︎