NUP155

NUP155 is a structurally essential nucleoporin that localizes symmetrically to both the nucleoplasmic and cytoplasmic faces of the nuclear pore complex (NPC) and disperses to the cytoplasm during mitosis (PMID:8458861). It is required for nuclear envelope formation and sealing: its depletion blocks nuclear lamina assembly, nucleoporin accumulation at the nuclear periphery, and formation of a continuous nuclear membrane, and it is recruited to chromatin late in NPC assembly at the time of membrane sealing (PMID:16193066). NUP155 is organized into functionally distinct domains—a β-propeller that anchors it to the assembling pore through Nup53 (with additional Nup93 contacts), and an α-solenoid that independently positions inner nuclear membrane proteins such as LBR and otefin and binds chromatin most strongly at mitotic exit (PMID:22718353, PMID:24363447). At the pore, NUP155 directly binds and anchors the mRNA export factor GLE1 at the nuclear rim, coupling it to the mRNA export machinery (PMID:14645504). Through this scaffolding role NUP155 supports bidirectional nucleocytoplasmic transport, including export of HSP70 mRNA and import of HSP70 protein (PMID:19070573). Its retention at the nuclear envelope and transport function depend on a direct interaction with lamin A/C (PMID:30488537). A homozygous R391H mutation in NUP155 causes atrial fibrillation and early sudden cardiac death by reducing nuclear localization, lowering nuclear envelope permeability, and impairing HSP70 mRNA/protein transport, a phenotype recapitulated by an AF-associated lamin A/C mutation that disrupts the lamin A/C–NUP155 interaction (PMID:19070573, PMID:30488537). Beyond its transport scaffolding role, NUP155 has been linked to gene-specific outputs, including translational control of p21 via transcriptional regulation of FTSJ1 within the p53 network (PMID:31089132) and nuclear export of INO80 mRNA in podocyte homeostasis (PMID:39111625).

1. 1993 High

   Establishing that NUP155 is a bona fide integral NPC component answered where the protein resides and set it apart from peripheral, WGA-reactive nucleoporins.

   Evidence Molecular cloning, immunoelectron microscopy, and urea/EDTA fractionation of rat liver nuclear envelopes

   PMID:8458861

   Open questions at the time

   • Did not define molecular partners or assembly determinants
   • Functional role in transport or assembly not yet addressed
2. 2003 Medium

   Identifying GLE1 as a direct NUP155 partner answered how an mRNA export factor is anchored to the pore, linking NUP155 to the mRNA export pathway.

   Evidence Yeast two-hybrid screen with in vitro binding, deletion mapping, and HeLa localization

   PMID:14645504

   Open questions at the time

   • Single lab; reciprocal in vivo validation limited
   • Whether GLE1 anchoring fully accounts for NUP155 transport function not resolved
3. 2005 High

   Depletion across two model systems answered whether NUP155 is required for nuclear envelope and NPC biogenesis, placing it at the late, membrane-sealing step of assembly.

   Evidence RNAi in C. elegans, Xenopus egg extract assays, EM, and chromatin-recruitment time course

   PMID:16193066

   Open questions at the time

   • Molecular partners mediating chromatin recruitment not defined here
   • Domain responsible for membrane sealing not mapped
4. 2008 High

   A human R391H mutation and mouse knockout answered whether NUP155 loss causes disease, tying impaired nucleocytoplasmic transport to atrial fibrillation and sudden death.

   Evidence Human genetic mapping with co-segregation, mouse knockout, nuclear permeability and HSP70 mRNA/protein transport assays

   PMID:19070573

   Open questions at the time

   • Mechanism linking transport defect to cardiac electrophysiology not detailed
   • Why HSP70 cargo specifically is affected not resolved
5. 2012 Medium

   Domain dissection answered how NUP155 partitions its jobs, separating NPC anchoring (β-propeller) from INM protein organization and chromatin binding (α-solenoid).

   Evidence Drosophila hypomorphic RNAi, rescue with deletion constructs, binding and chromatin-extract assays

   PMID:22718353

   Open questions at the time

   • Chromatin-binding partner not identified
   • Single lab in Drosophila; human domain equivalence assumed
6. 2013 High

   Mapping the Nup53–NUP155 interaction answered how NUP155 is recruited to the assembling pore, identifying Nup53 as the principal recruitment determinant.

   Evidence Co-IP, in vitro binding, domain deletion, and Xenopus NPC assembly reconstitution

   PMID:24363447

   Open questions at the time

   • Order of recruitment relative to membrane events not fully resolved
   • Stoichiometry within the assembled pore not defined
7. 2018 Medium

   Demonstrating a direct lamin A/C–NUP155 interaction answered how NUP155 is retained at the nuclear envelope and provided a second genetic route to the AF transport phenotype.

   Evidence Co-IP, GST pull-down, NE fractionation, and HSP70 mRNA/protein transport assays with an AF lamin A/C mutant

   PMID:30488537

   Open questions at the time

   • Single lab; structural basis of the interaction unknown
   • Whether lamin A/C tethering is direct or via other NPC components not fully separated
8. 2019 Medium

   Linking NUP155 to FTSJ1 and p21 translation answered whether NUP155 has gene-regulatory outputs beyond bulk transport, embedding it in the p53 network.

   Evidence Proteomics, polysome fractionation, RNAi, and transcriptional reporters in hepatocellular carcinoma cells

   PMID:31089132

   Open questions at the time

   • Mechanism by which a nucleoporin transcriptionally regulates FTSJ1 not defined
   • Generality beyond HCC cells unknown
9. 2024 Medium

   Podocyte studies answered whether NUP155-dependent mRNA export controls cell fate, linking impaired INO80 mRNA export to senescence.

   Evidence siRNA, overexpression rescue, mRNA export assays, EM, and ferulic acid binding in podocytes

   PMID:39111625

   Open questions at the time

   • Selectivity for INO80 mRNA mechanistically unexplained
   • Direct ferulic acid binding mode not structurally resolved
10. 2024 Medium

    TRIM21-directed degradation answered whether targeted NUP155 destruction is cytotoxic, with GLE1 lost as a passenger and nuclear envelope integrity collapsing.

    Evidence DEL screen, TRIM21-ligand crystallography, proteomics, and proteasome-inhibitor rescue (preprint)

    PMID:bio_10.1101_2024.12.03.626577

    Open questions at the time

    • Preprint, not peer-reviewed
    • Therapeutic window and selectivity not established

• How NUP155 achieves cargo- and transcript-specific outputs (HSP70, INO80 mRNA, FTSJ1/p21) from a structural scaffolding role remains unresolved.
• No mechanism connecting NPC scaffolding to selective transcript regulation
• Structural model of the human NUP155 β-propeller/α-solenoid in the assembled pore lacking
• Direct chromatin-binding partner of the α-solenoid unidentified