NUP153 — Nucleoporin 153

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<table class="infobox infobox-gene">
<tr><th class="infobox-header" colspan="2">NUP153</th></tr>
<tr><td class="label">Full Name</td><td>Nucleoporin 153</td></tr>
<tr><td class="label">Chromosome</td><td>6p22.3</td></tr>
<tr><td class="label">NCBI Gene ID</td><td><a href="https://www.ncbi.nlm.nih.gov/gene/9972" target="_blank">9972</a></td></tr>
<tr><td class="label">Ensembl ID</td><td>ENSG00000124789</td></tr>
<tr><td class="label">OMIM ID</td><td>603948</td></tr>
<tr><td class="label">UniProt ID</td><td><a href="https://www.uniprot.org/uniprot/P49790" target="_blank">P49790</a></td></tr>
<tr><td class="label">Associated Diseases</td><td>[ALS](/diseases/als), [FTD](/diseases/ftd), [Alzheimer's Disease](/diseases/alzheimers-disease), [Huntington's Disease](/diseases/huntingtons-disease)</td></tr>
</table>

NUP153 — Nucleoporin 153

Overview

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NUP153 — Nucleoporin 153

Overview

Mermaid diagram (expand to render)

NUP153 encodes nucleoporin 153, a critical component of the nuclear basket structure of the nuclear pore complex (NPC). As a dynamic phenylalanine-glycine (FG)-repeat nucleoporin positioned at the nuclear face of the NPC, NUP153 plays essential roles in nuclear import, mRNA export, chromatin organization, and DNA damage repair. NUP153 dysfunction is increasingly recognized as a convergent pathological feature of multiple neurodegenerative diseases, particularly in [C9orf72](/genes/c9orf72)-associated [amyotrophic lateral sclerosis](/diseases/als) (ALS) and [frontotemporal dementia](/diseases/ftd) (FTD), where nuclear transport deficits represent a primary disease mechanism["@fahrenkrog2004"][@zhang2015].

NUP153 serves as a key docking site for nuclear import receptors including importin-alpha/beta and transportin-1, facilitating the translocation of transcription factors, RNA-binding proteins, and DNA repair enzymes into the nucleus. Its depletion leads to nuclear accumulation of RNA, cytoplasmic mislocalization of nuclear proteins, and impaired DNA damage responses—all hallmarks of neurodegenerative pathology["@bastos1996"].

Gene Structure and Expression

NUP153 is located on chromosome 6p22.3 and spans approximately 65 kb. The gene encodes a 1,475-amino acid protein with a molecular weight of approximately 153 kDa. The protein contains three structurally and functionally distinct domains:

N-terminal domain (residues 1-149): Contains the nuclear pore targeting domain that anchors NUP153 to the nuclear basket through interactions with [NUP107](/genes/nup107)-NUP160 Y-complex
Zinc finger domain (residues 650-880): Contains four C₂H₂-type zinc fingers that bind RNA and DNA, mediating chromatin association at the nuclear periphery and direct interactions with specific genomic loci including superenhancers
C-terminal FG-repeat domain (residues 880-1475): Contains approximately 29 FG-repeat motifs that interact with nuclear transport receptors (importins and exportins) to facilitate cargo translocation through the NPC

NUP153 is highly expressed in post-mitotic [neurons](/entities/neurons), where NPCs are extraordinarily long-lived. Unlike dividing cells where NPC components are renewed during mitosis, neurons must maintain NUP153 through protein quality control mechanisms throughout their lifespan, making them especially vulnerable to age-related NUP153 dysfunction. Expression is particularly high in the [hippocampus](/brain-regions/hippocampus), [cortex](/brain-regions/cerebral-cortex), and [motor neurons](/cell-types/motor-neurons)[@dangelo2009].

Function and Mechanism

Nuclear Transport Regulation

NUP153 functions as a mobile nucleoporin that rapidly associates with and dissociates from the NPC (residence time ~seconds to minutes), in contrast to scaffold nucleoporins that remain stably associated for months. This dynamic behavior allows NUP153 to actively participate in transport:

Import facilitation: NUP153 FG-repeats provide binding sites for importin-β family members, creating a kinetic pathway that accelerates cargo translocation. Key neuronal cargoes dependent on NUP153 include [TDP-43](/proteins/tdp-43), [FUS](/genes/fus), and hnRNP family members
mRNA export: NUP153 interacts with the TREX-2/GANP mRNA export complex and is required for efficient export of poly(A)+ RNA, including transcripts encoding synaptic proteins
Selective export of stress-responsive mRNAs: Under stress conditions, NUP153 preferentially facilitates export of heat shock and DNA damage response transcripts

Chromatin Organization at the Nuclear Periphery

NUP153 zinc finger domains directly bind chromatin at specific genomic loci, positioning superenhancers and developmentally regulated genes near the nuclear pore for efficient transcriptional activation and mRNA export. In neurons, NUP153-associated chromatin domains include genes required for synaptic plasticity and [long-term potentiation](/mechanisms/long-term-potentiation), including [BDNF](/genes/bdnf), [ARC](/genes/arc), and [FOS](/genes/fos). Loss of NUP153-chromatin interactions leads to gene silencing and impaired activity-dependent transcription[@ibarra2016].

DNA Damage Response

NUP153 is essential for the nucleocytoplasmic transport of DNA repair factors, particularly in the homologous recombination pathway. It facilitates nuclear import of [BRCA1](/genes/brca1), 53BP1, and RAD51, and is required for mobilization of damaged DNA to the nuclear periphery where repair occurs in association with the NPC. In aging neurons, NUP153 decline contributes to accumulation of DNA damage and genomic instability[@lemaitre2012].

Disease Associations

The [C9orf72](/genes/c9orf72) hexanucleotide repeat expansion (GGGGCC)ₙ, the most common genetic cause of ALS and FTD, directly impairs NUP153 function through multiple mechanisms:

Dipeptide repeat protein toxicity: Poly-PR and poly-GR dipeptide repeat proteins translated from the repeat expansion bind FG-repeat domains of NUP153 and other FG-nucleoporins, obstructing the NPC channel and impairing both import and export
RNA foci sequestration: Sense and antisense repeat RNA foci sequester RNA-binding proteins including [RANGAP1](/genes/rangap1) and NUP153-interacting transport factors, disrupting the Ran-GTP gradient essential for directional transport
NUP153 mislocalization: In [C9orf72](/entities/c9orf72) patient motor neurons, NUP153 shows cytoplasmic punctate accumulation rather than normal nuclear rim localization, indicating NPC structural breakdown

Restoration of NUP153 levels rescues nuclear transport deficits and neuronal survival in C9orf72 iPSC-derived motor neuron models[@zhang2015][@freibaum2015].

Alzheimer's Disease

In AD, NUP153 protein levels decline with age and are further reduced in neurons bearing [tau](/proteins/tau) pathology. Hyperphosphorylated [tau](/proteins/tau) disrupts the nuclear lamina and NPC architecture, leading to NUP153 displacement from the nuclear envelope and accumulation of cytoplasmic NPC components. This results in:

Impaired nuclear import of transcription factors required for synaptic maintenance
Nuclear retention of mRNAs encoding synaptic and survival proteins
Loss of NUP153-mediated chromatin organization, contributing to epigenetic dysregulation
Impaired DNA repair factor import, accelerating genomic instability

Huntington's Disease

Mutant [huntingtin](/proteins/huntingtin) protein with expanded polyglutamine tracts physically disrupts NPCs and sequesters NUP153 in cytoplasmic aggregates. NUP153 is among the nucleoporins most depleted from the nuclear envelope in HD models, and its loss correlates with the severity of nuclear transport impairment in medium spiny neurons[@grima2017].

Aging

NUP153 is a critical node in age-related NPC deterioration. NPCs in post-mitotic neurons are among the longest-lived protein complexes in the body, with estimated half-lives exceeding years. NUP153, as a dynamic nucleoporin, is more susceptible to oxidative damage and turnover failure than scaffold components. Age-related loss of NUP153 has been directly linked to nuclear transport decline, accumulation of cytoplasmic [TDP-43](/proteins/tdp-43), and loss of nuclear envelope integrity in aging neurons[@dangelo2009].

Therapeutic Implications

NUP153 represents a compelling therapeutic target for restoring nuclear transport in neurodegeneration:

NUP153 gene therapy: AAV-mediated NUP153 overexpression rescues nuclear transport deficits in C9orf72 ALS motor neuron models
Nuclear transport modifiers: Small molecules that enhance importin-β-NUP153 FG-repeat interactions could boost transport capacity in aging neurons
Exportin inhibitors: Selective inhibitors of nuclear export (KPT-350, SINE compounds) partially compensate for NUP153 import deficits by preventing nuclear protein leakage
[Autophagy](/entities/autophagy)-NPC quality control: Enhancing selective autophagy of damaged NPC components could promote NUP153 turnover and NPC renewal

External Links

[NCBI Gene: NUP153](https://www.ncbi.nlm.nih.gov/gene/9972)
[UniProt: P49790](https://www.uniprot.org/uniprot/P49790)
[OMIM: 603948](https://omim.org/entry/603948)
[GeneCards: NUP153](https://www.genecards.org/cgi-bin/carddisp.pl?gene=NUP153)

References

[Fahrenkrog et al., The nuclear pore complex, nuclear transport, and apoptosis (2004) (2004)](https://doi.org/10.1139/o04-018)

[Zhang et al., The C9orf72 repeat expansion disrupts nucleocytoplasmic transport (2015) (2015)](https://doi.org/10.1038/nature15723)

[Bastos et al., Targeting and function in mRNA export of nuclear pore complex protein Nup153 (1996) (1996)](https://doi.org/10.1083/jcb.134.5.1141)

[D'Angelo et al., Age-dependent deterioration of nuclear pore complexes causes a loss of nuclear integrity in postmitotic cells (2009) (2009)](https://doi.org/10.1016/j.cell.2009.01.037)

[Ibarra et al., Nucleoporin-mediated regulation of cell identity genes (2016) (2016)](https://doi.org/10.1101/gad.287417.116)

[Lemaitre et al., The nucleoporin 153, a novel factor in double-strand break repair and DNA damage response (2012) (2012)](https://doi.org/10.1038/onc.2011.519)

[Freibaum et al., GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport (2015) (2015)](https://doi.org/10.1038/nature15723)

[Grima et al., Mutant Huntingtin disrupts the nuclear pore complex (2017) (2017)](https://doi.org/10.1016/j.neuron.2017.03.023)

[Toyama et al., Identification of long-lived proteins reveals exceptional stability of essential cellular structures (2013) (2013)](https://doi.org/10.1016/j.cell.2013.11.021)

[Gasset-Rosa et al., Polyglutamine-expanded huntingtin exacerbates age-related disruption of nuclear integrity and nucleocytoplasmic transport (2017) (2017)](https://doi.org/10.1016/j.neuron.2017.06.027)

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NUP153 — Nucleoporin 153

NUP153 — Nucleoporin 153

Overview

NUP153 — Nucleoporin 153

Overview

Gene Structure and Expression

Function and Mechanism

Nuclear Transport Regulation

Chromatin Organization at the Nuclear Periphery

DNA Damage Response

Disease Associations

ALS and FTD (C9orf72-Related)

Alzheimer's Disease

Huntington's Disease

Aging

Therapeutic Implications

See Also

External Links

References