NUP133

NUP133 is a scaffold nucleoporin of the conserved Y-complex (Nup107-160 complex) that builds the structural core of the nuclear pore complex (NPC) and supports nucleocytoplasmic transport (PMID:11684705, PMID:7626806, PMID:7862658). It integrates into the NPC scaffold through a tight tail-to-tail interface between its C-terminal alpha-helical domain and Nup107, which serves as the critical anchor positioning NUP133 at the NPC periphery (PMID:15557116, PMID:18570875). Its N-terminal seven-bladed beta-propeller domain harbors an amphipathic lipid packing sensor (ALPS) motif that binds membranes directly, anchoring the NPC to the curved nuclear envelope membrane (PMID:15557116, PMID:25139911, PMID:33247142). Beyond scaffolding, NUP133 is required for mRNA export and for proper NPC distribution within the nuclear envelope, since loss of function causes nuclear accumulation of poly(A)+ RNA and clustering of pores (PMID:11684705, PMID:7626806, PMID:7862658). Its central domain promotes nuclear basket assembly by enabling stable incorporation of Tpr and proper Nup153 dynamics (PMID:29791854), while its N-terminal domain performs a mitotic role, recruiting the dynein/dynactin complex to the nuclear envelope in prophase via a CENP-F and NudE/NudEL network to tether centrosomes and support bipolar spindle assembly (PMID:21383080). Loss-of-function and partial-loss-of-function mutations in NUP133, which impair NUP133-NUP107/Y-complex interactions, cause a Mendelian disease spectrum including steroid-resistant nephrotic syndrome and neurodevelopmental phenotypes, recapitulated by disrupted NPC assembly and altered cell-type-specific function in podocytes and in zebrafish (PMID:30427554, PMID:35455939).

1. 1995 High

   Established the first functional role for Nup133 by showing it is needed for both mRNA export and proper spatial organization of NPCs within the nuclear envelope.

   Evidence Temperature-sensitive yeast mutants and gene disruption with poly(A)+ RNA FISH, immunofluorescence, and EM

   PMID:7626806 PMID:7862658

   Open questions at the time

   • Did not define the protein partners or domains mediating these functions
   • Mechanistic link between scaffold integration and mRNA export left open
2. 2001 High

   Placed vertebrate Nup133 within a defined nucleoporin subcomplex and showed it directly contributes to mRNA export, generalizing the yeast role to metazoans.

   Evidence Pulldown/co-IP from Xenopus egg extracts plus dominant-negative fragment transport assays

   PMID:11684705

   Open questions at the time

   • Did not resolve which Nup133 domain contacts which complex member
   • No structural basis for complex assembly
3. 2004 High

   Resolved the bipartite domain organization of human Nup133, separating an NPC-integration function (C-terminal) from a protein-interaction beta-propeller (N-terminal).

   Evidence Crystal structure of the N-terminal beta-propeller and domain interaction mapping

   PMID:15557116

   Open questions at the time

   • Functional partners of the beta-propeller surface not identified
   • No structure of the C-terminal Nup107-binding region
4. 2008 High

   Defined the molecular basis of NPC scaffold integration by solving the Nup107-Nup133 C-terminal interface and showing Nup107 is the critical anchor.

   Evidence Crystal structure of the Nup107-Nup133 C-terminal complex with structure-guided mutagenesis and binding assays

   PMID:18570875

   Open questions at the time

   • Did not address membrane attachment of the assembled scaffold
   • In-cell consequences of interface mutants not fully mapped
5. 2009 Medium

   Positioned Nup133 within the evolutionary architecture of the NPC, identifying a shared ancestral alpha-helical building block with Nup157/170.

   Evidence Comparative crystal structure analysis of yNup170 and hNup107-Nup133

   PMID:19674973

   Open questions at the time

   • Evolutionary inference without functional mutagenesis
   • Does not establish a distinct cellular function
6. 2011 High

   Revealed a mitosis-specific moonlighting function: the N-terminal domain anchors dynein/dynactin to the nuclear envelope to tether centrosomes and promote bipolar spindle assembly.

   Evidence Dominant-negative constructs, reciprocal co-IPs defining the CENP-F/NudE-NudEL network, siRNA, and live-cell imaging

   PMID:21383080

   Open questions at the time

   • Direct binding partner of the Nup133 N-terminus within the network not pinpointed
   • How interphase scaffold role and mitotic role are coordinated unknown
7. 2014 Medium

   Provided a full-length structural model of yeast Nup133 and identified an ALPS motif in the N-terminal region as a candidate membrane-anchoring element for the NPC.

   Evidence Integrative modeling (crystal structures, SAXS, negative-stain EM) with mutational studies and cross-linking MS

   PMID:25139911

   Open questions at the time

   • Membrane-anchoring activity not directly reconstituted in this study
   • Conservation to human ALPS not yet shown
8. 2018 High

   Demonstrated a discrete scaffold-independent role in nuclear basket assembly mediated by the central domain, linking Nup133 to Tpr incorporation and Nup153 dynamics.

   Evidence CRISPR-null mESCs with single-pore fluorescence detection, Nup153 FRAP, and domain-specific rescue constructs

   PMID:29791854

   Open questions at the time

   • Why only ~half of NPCs require Nup133 for Tpr incorporation is unexplained
   • Molecular mechanism connecting central domain to basket recruitment unknown
9. 2018 Medium

   Connected NUP133 to human disease, showing a splicing mutation impairs the NUP133-NUP107 interaction and causes neurodevelopmental and renal phenotypes correctable by wild-type but not mutant protein.

   Evidence Immunoprecipitation of mutant interaction plus zebrafish morphant rescue with WT vs mutant human mRNA

   PMID:30427554

   Open questions at the time

   • Cell-type-specific mechanism linking NPC defect to phenotypes not resolved
   • Morpholino-based knockdown rather than stable genetic model
10. 2020 High

    Confirmed direct membrane binding by the conserved N-terminal ALPS motif, establishing it as a genuine membrane-anchoring element of the Y complex.

    Evidence Cryo-EM/nanobody-bound crystal structures with liposome interaction assays

    PMID:33247142

    Open questions at the time

    • In-cell contribution of ALPS-mediated anchoring to NPC stability not quantified
    • Regulation of membrane engagement during pore assembly unclear
11. 2020 Low

    Proposed a transcriptional/stress-response link in which Nup133 levels influence Nrf1 expression in oligodendrocyte progenitors under hyperoxia.

    Evidence Hyperoxia treatment of primary OPCs with western blot, mRNA quantification, and knockdown/overexpression

    PMID:32844334

    Open questions at the time

    • Correlation-based with limited mechanistic follow-up; direct regulation of Nrf1 not biochemically established
    • Sex-differential effect mechanism unresolved
12. 2022 Medium

    Linked NUP133 loss-of-function to podocyte dysfunction, tying impaired NPC assembly and Y-complex interactions to altered transcriptome and defective cell protrusions in SRNS.

    Evidence CRISPR/Cas9 knockout in human podocytes with transcriptomics, NPC assembly assays, protrusion/cytoskeleton readouts, and interaction analysis

    PMID:35455939

    Open questions at the time

    • Direct mechanistic chain from NPC defect to protrusion failure not fully resolved
    • Single cell-type model

• How NUP133's distinct domain functions (scaffold integration, membrane anchoring, basket assembly, mitotic dynein recruitment, and putative transcriptional effects) are coordinated and how partial loss-of-function selectively impairs specialized cell types remain open.
• No unified model linking domain-specific activities to tissue-specific disease
• Mechanism of selective NPC clustering versus mRNA export defect unresolved
• Direct transcriptional regulation activity not biochemically established