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](/diseases/als), [FTD](/diseases/ftd), [Alzheimer's Disease](/diseases/alzheimers-disease), Acute Febrile Encephalopathy

NUP214 — Nucleoporin 214

Overview

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^{1Nup214-Nup88 nucleoporin subcomplex is required for CRM1-mediated 60S preribosomal nuclear export (2006)2006 · DOI 10.1074/jbc.M603338200Open reference2The C9orf72 repeat expansion disrupts nucleocytoplasmic transport (2015)2015 · DOI 10.1038/nature15723Open reference}.

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^{3Autoimmune encephalitis associated with antibodies against nucleoporin p62 and NUP214 (2023)2023 · DOI 10.1016/j.jneuroim.2023.578098Open reference}.

Gene Structure and Expression

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:

• N-terminal β-propeller domain (residues 1-450): Forms a seven-bladed β-propeller structure that mediates stable incorporation into the NPC outer ring through interactions with NUP88

• Coiled-coil region (residues 450-1200): Contains extensive coiled-coil domains that form the cytoplasmic filament stalk, projecting ~50 nm from the NPC into the cytoplasm

• C-terminal FG-repeat domain (residues 1200-2090): Contains ~40 FG-repeat motifs that serve as the primary docking site for the CRM1/XPO1 exportin loaded with cargo bearing leucine-rich nuclear export signals (NES)

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^{4Identification of long-lived proteins reveals exceptional stability of essential cellular structures (2013)2013 · DOI 10.1016/j.cell.2013.11.021Open reference}.

Function and Mechanism

Nuclear Export Regulation

NUP214 serves as the terminal docking site in the nuclear export pathway. The export process proceeds through a defined series of interactions:

1. In the nucleus, CRM1/XPO1 binds cargo proteins bearing NES sequences in a RanGTP-dependent manner

2. The CRM1-cargo-RanGTP complex traverses the NPC central channel through interactions with channel FG-nucleoporins (NUP62, NUP58, NUP54)

3. At the cytoplasmic face, the complex docks to NUP214 FG-repeats, where RanGAP1-mediated GTP hydrolysis triggers cargo release

4. Dissociated CRM1 recycles back to the nucleus for another round of export

Key neuronal cargoes exported through the NUP214-CRM1 pathway include:

• mRNA-protein complexes: Transcripts encoding PSD-95, AMPA receptors, and NMDA receptors required for synaptic function

• Signal transduction molecules: Activated MAPK/ERK pathway components that shuttle between nucleus and cytoplasm

• RNA-binding proteins: TDP-43, FUS, and hnRNP family members that cycle between nuclear RNA processing and cytoplasmic translation regulation

Ribosomal Subunit Export

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^{5Ultrastructural localization of rRNA shows defective nuclear export of preribosomes in mutants of the Nup82p complex (2001)2001 · DOI 10.1083/jcb.155.6.923Open reference}.

mRNA Surveillance

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.

Disease Associations

ALS and FTD

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:

• Nuclear retention of mRNAs, causing progressive loss of cytoplasmic protein synthesis

• Cytoplasmic accumulation of CRM1 and Ran-GTP, depleting the nuclear Ran-GTP pool required for import

• Nuclear accumulation of proteins that require CRM1-dependent export, disrupting their cytoplasmic functions

• Selective vulnerability of motor neurons, which have among the highest mRNA export demands of any cell type

In patient-derived motor neurons, NUP214 mislocalization from the nuclear envelope to cytoplasmic puncta is an early pathological feature that precedes TDP-43 aggregation^{2The C9orf72 repeat expansion disrupts nucleocytoplasmic transport (2015)2015 · DOI 10.1038/nature15723Open reference6GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport (2015)2015 · DOI 10.1038/nature15723Open reference}.

Alzheimer’s Disease

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.

Autoimmune NUP214 Encephalitis

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^{3Autoimmune encephalitis associated with antibodies against nucleoporin p62 and NUP214 (2023)2023 · DOI 10.1016/j.jneuroim.2023.578098Open reference}.

Acute Leukemias

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.

Therapeutic Implications

• CRM1/XPO1 modulators: Selective inhibitors of nuclear export (KPT-350, selinexor) can paradoxically compensate for NUP214 export pathway blockade by reducing overall export demand and retaining protective nuclear factors

• NUP214-targeted gene therapy: AAV-mediated delivery of NUP214 C-terminal FG-repeat domains could serve as decoy substrates for dipeptide repeat protein binding, protecting endogenous NUP214

• Antisense oligonucleotides: ASOs targeting C9orf72 repeat RNA reduce dipeptide repeat protein production and prevent NUP214 obstruction in preclinical models

• NPC quality control enhancement: Promoting selective autophagy of damaged NPC components through ESCRT-III pathway activation could restore NUP214 function

See Also

• NUP62 — Central channel nucleoporin, also disrupted in ALS/FTD

• NUP153 — Nuclear basket nucleoporin involved in import

• NUP98 — FG-nucleoporin with dual import/export roles

• C9orf72 — Repeat expansion disrupts NUP214 function

• CRM1/XPO1 — Primary export receptor docking at NUP214

• Nuclear Transport Defects — Convergent neurodegeneration mechanism

External Links

• NCBI Gene: NUP214

• UniProt: P35658

• OMIM: 114350

• GeneCards: NUP214