UBXN2B

UBXN2B (p37) is a cofactor of the p97/VCP AAA-ATPase that couples p97 to mitotic and proteostatic functions across cellular compartments (PMID:29222185, PMID:38701207). During mitosis, p37 controls spindle orientation by limiting the levels of cortical NuMA: it negatively regulates the PP1 phosphatase and its regulatory subunit Repo-Man, acting independently of Gαi, Aurora A kinase, and PP2A, such that the PP1/Repo-Man-driven cortical NuMA accumulation seen in anaphase is restrained in metaphase (PMID:29222185). Beyond mitosis, p37 is a major determinant of p97 nucleocytoplasmic shuttling, and this distribution is required for both cytosolic p97 functions (autophagy) and nuclear p97 functions (DNA damage repair); multisystem proteinopathy-associated VCP mutations enhance VCP–p37 association, reducing nuclear VCP and increasing DNA damage susceptibility, defects normalized by lowering p37 (PMID:38701207). p37 acts within a p97 complex alongside the FAM104 proteins VCF1/2, which associate with both p97-UFD1-NPL4 and p97-UBXN2B assemblies and promote nuclear import of p97 (PMID:37713320).

1. 2017 High

   Established that the p97 cofactor p37 has a dedicated mitotic role, defining how spindle orientation is set by restraining cortical NuMA through a specific phosphatase axis.

   Evidence RNAi loss-of-function with spindle-orientation readout and cortical NuMA imaging, plus epistasis placing p37 upstream of PP1/Repo-Man and independent of Gαi, Aurora A, and PP2A

   PMID:29222185

   Open questions at the time

   • Whether p37 regulates PP1/Repo-Man via p97 ATPase activity or independently is not resolved
   • Direct biochemical demonstration of p37 acting on the PP1/Repo-Man complex is absent
   • Does not address how this mitotic function relates to p37's interphase p97 roles
2. 2023 Medium

   Identified the molecular machinery delivering p97 to the nucleus, placing UBXN2B in a defined complex with VCF1/2 that promotes p97 nuclear import.

   Evidence Co-immunoprecipitation and mass spectrometry defining the p97-UBXN2B-VCF1/2 complex, with nuclear p97 quantification upon VCF1/2 loss

   PMID:37713320

   Open questions at the time

   • Single study with two orthogonal methods; reciprocal validation of complex membership in vitro not shown
   • Mechanism by which VCF1/2 drives import (carrier vs. retention) is unresolved
   • Functional consequences of the p37-VCF1/2 axis for downstream p97 activities not tested here
3. 2024 High

   Demonstrated that p37 governs p97 nucleocytoplasmic distribution as a control point for both autophagy and DNA damage repair, linking the cofactor to disease-associated VCP dysfunction.

   Evidence Subcellular fractionation, live imaging, Co-IP, autophagy flux and DNA damage sensitivity assays, with p37 knockdown rescue in mutant VCP cell lines

   PMID:38701207

   Open questions at the time

   • Whether p37 acts as a cytoplasmic retention factor or active shuttling carrier is not distinguished
   • Molecular basis for enhanced p37 association by MSP VCP mutants not structurally defined
   • Relationship between the mitotic NuMA function and the shuttling function in the same cells unexamined

• How p37's mitotic spindle-orientation role, its control of p97 localization, and the VCF1/2-dependent nuclear import pathway are mechanistically integrated remains unresolved.
• No structural model of the p97-UBXN2B-VCF1/2 complex
• Direct substrates processed by p97 under p37 control are not identified
• Whether p37 binding to p97 is required for the PP1/Repo-Man regulation is untested