| NUP214 | |
|---|---|
| Full Name | Nucleoporin 214 (CAN) |
| Chromosome | 9q34.13 |
| NCBI Gene ID | 8021 |
| Ensembl ID | ENSG00000126883 |
| OMIM ID | 114350 |
| UniProt ID | P35658 |
| Associated Diseases | ALS, FTD, Alzheimer's Disease, Acute Febrile Encephalopathy |
NUP214 (also known as CAN) encodes nucleoporin 214, a large FG-repeat nucleoporin that forms the cytoplasmic filaments of the nuclear pore complex (NPC). NUP214 is the principal docking site for CRM1/XPO1-mediated nuclear export, making it essential for the cytoplasmic delivery of mRNAs, ribosomal subunits, and proteins bearing nuclear export signals. In the nervous system, NUP214 is critical for the export of synaptic protein mRNAs and the maintenance of RNA homeostasis in post-mitotic neurons[1][2].
NUP214 has garnered significant attention in neurodegeneration research due to its vulnerability to disruption by pathological protein aggregates, particularly the dipeptide repeat proteins generated from C9orf72 repeat expansions. Additionally, autoimmune encephalitis targeting NUP214 demonstrates that antibody-mediated disruption of this nucleoporin alone is sufficient to cause severe neurological dysfunction, underscoring its non-redundant role in neuronal survival[3].
NUP214 is located on chromosome 9q34.13 and spans approximately 110 kb of genomic DNA. The gene encodes a 2,090-amino acid protein with a molecular weight of approximately 214 kDa. The protein has a modular architecture:
NUP214 is expressed in all tissues but is particularly critical in neurons due to their dependence on efficient mRNA export for synaptic protein synthesis. The protein has an exceptionally long half-life in post-mitotic neurons, with estimates exceeding several years, making it susceptible to cumulative oxidative damage and age-related functional decline[4].
NUP214 serves as the terminal docking site in the nuclear export pathway. The export process proceeds through a defined series of interactions:
Key neuronal cargoes exported through the NUP214-CRM1 pathway include:
NUP214 is essential for the export of pre-60S ribosomal subunits. In neurons with high translational demands, particularly at synapses where local protein synthesis is required for plasticity, NUP214 dysfunction leads to ribosomal insufficiency and translational failure[5].
NUP214 participates in mRNA quality control at the cytoplasmic face of the NPC. Aberrant mRNAs that fail to be properly processed are retained at NUP214-containing cytoplasmic filaments for degradation by the nonsense-mediated decay machinery, preventing translation of potentially toxic truncated proteins.
NUP214 is a primary target of C9orf72 repeat expansion-derived toxicity. Poly-PR dipeptide repeat proteins have high affinity for FG-repeat domains and accumulate at NUP214, physically blocking the CRM1 docking site and preventing cargo release. This results in:
In patient-derived motor neurons, NUP214 mislocalization from the nuclear envelope to cytoplasmic puncta is an early pathological feature that precedes TDP-43 aggregation[2:1][6].
In AD, NUP214 undergoes age-related oxidative modifications that reduce its affinity for CRM1. Combined with tau-mediated disruption of the nuclear lamina, NUP214 oxidation contributes to progressive nuclear export failure in hippocampal neurons. This export deficit leads to nuclear accumulation of misfolded proteins and impaired delivery of synaptic protein mRNAs to the cytoplasm.
Anti-NUP214 antibodies cause acute febrile encephalopathy, demonstrating that isolated NUP214 dysfunction is sufficient for severe neurological disease. Patients present with acute encephalopathy, movement disorders, and seizures. The syndrome provides a human knockout model illustrating NUP214's essential role in neuronal function and suggests that even partial NUP214 impairment could contribute to chronic neurodegeneration[3:1].
NUP214 fusions (NUP214-ABL1, SET-NUP214) are recurrent in T-cell acute lymphoblastic leukemia. While primarily oncological, these fusions demonstrate that NUP214 truncation disrupts nuclear transport homeostasis with severe cellular consequences.
Bernad et al. Nup214-Nup88 nucleoporin subcomplex is required for CRM1-mediated 60S preribosomal nuclear export (2006). 2006. ↩︎
Zhang et al. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport (2015). 2015. ↩︎ ↩︎
Neri et al. Autoimmune encephalitis associated with antibodies against nucleoporin p62 and NUP214 (2023). 2023. ↩︎ ↩︎
Toyama et al. Identification of long-lived proteins reveals exceptional stability of essential cellular structures (2013). 2013. ↩︎
Gleizes et al. Ultrastructural localization of rRNA shows defective nuclear export of preribosomes in mutants of the Nup82p complex (2001). 2001. ↩︎
Freibaum et al. GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport (2015). 2015. ↩︎