UBXN2B

UBXN2B (p37) is a UBX-domain-containing substrate adaptor/cofactor of the AAA ATPase p97/VCP that coordinates organelle biogenesis, mitotic progression, and p97 subcellular distribution. The p97/p37 complex possesses membrane fusion activity required for Golgi and ER biogenesis during interphase and organelle reassembly at mitotic exit, a function inhibited when Cdc2 phosphorylates p37 on Ser56/Thr59 to block Golgi membrane binding and drive mitotic Golgi disassembly (PMID:17141156, PMID:20875789). UBXN2B limits centrosomal Aurora A recruitment through CDC-48/p97 to coordinate centrosome maturation timing and regulates spindle orientation by restricting cortical NuMA levels via negative regulation of PP1/Repo-Man (PMID:23649807, PMID:29222185). UBXN2B also controls p97 nucleocytoplasmic shuttling, which is required for both cytosolic autophagy and nuclear DNA damage repair; disease-causing VCP mutations enhance VCP–p37 association, reducing nuclear VCP and increasing DNA damage susceptibility (PMID:38701207).

1. 2006 High

   Identifying p37 as a p97 cofactor with membrane fusion activity resolved how Golgi and ER biogenesis are driven post-mitotically and during interphase, establishing a p97/p37-specific pathway distinct from the known p97/p47 route.

   Evidence In vitro Golgi reassembly assay, siRNA knockdown, antibody microinjection, pathway component epistasis in mammalian cells

   PMID:17141156

   Open questions at the time

   • Structural basis of p37 membrane recruitment is undefined
   • Whether p97/p37 directly drives ER tubule fusion or acts indirectly is unresolved
   • Relative contributions of p97/p37 vs p97/p47 to post-mitotic Golgi reassembly in vivo are unclear
2. 2010 High

   Demonstrating that Cdc2 phosphorylation of p37 on Ser56/Thr59 blocks Golgi membrane binding and membrane fusion activity explained how mitotic kinase signaling inactivates the p97/p37 pathway to promote Golgi disassembly at mitotic entry.

   Evidence Phosphomimetic mutagenesis (S56D/T59D), in vitro Golgi reassembly and membrane-binding assays, phosphorylation site mapping

   PMID:20875789

   Open questions at the time

   • Whether additional kinases phosphorylate p37 at mitosis is unknown
   • The phosphatase responsible for p37 dephosphorylation at mitotic exit is unidentified
   • In vivo validation of phospho-site mutant phenotypes has not been reported
3. 2013 High

   Showing that UBXN-2/p37 limits centrosomal Aurora A recruitment via CDC-48/p97 extended p37 function beyond membrane dynamics to mitotic spindle regulation and centrosome maturation timing.

   Evidence RNAi in C. elegans embryos and human cells, coimmunoprecipitation with Aurora A, genetic epistasis (double depletion rescue), Aurora A inhibitor rescue

   PMID:23649807

   Open questions at the time

   • Whether p37/p97 directly ubiquitin-dependently extracts Aurora A from centrosomes is unresolved
   • The substrate(s) of p97/p37 at centrosomes have not been identified
   • Whether p37 and p47 are redundant in centrosome regulation remains unclear
4. 2017 High

   Establishing that p37 restricts cortical NuMA levels through negative regulation of PP1/Repo-Man, independently of Gαi and Aurora A, defined a second mitotic spindle-orientation pathway controlled by p37.

   Evidence siRNA knockdown in mammalian cells, multi-step epistasis with PP1/Repo-Man, Aurora A inhibition, Gαi depletion, immunofluorescence quantification

   PMID:29222185

   Open questions at the time

   • Whether p37/p97 directly binds or extracts Repo-Man is unknown
   • The ubiquitin signal (if any) linking p97/p37 to PP1/Repo-Man regulation is uncharacterized
   • How p37-mediated NuMA restriction is relieved at anaphase is not established
5. 2024 High

   Demonstrating that p37 controls p97 nucleocytoplasmic distribution — required for both cytosolic autophagy and nuclear DNA damage repair — connected p37 to disease-relevant VCP pathology, as multisystem proteinopathy VCP mutations enhance VCP–p37 association and reduce nuclear VCP.

   Evidence siRNA knockdown, overexpression, subcellular fractionation, co-immunoprecipitation, DNA damage and autophagy flux assays in mammalian cells

   PMID:38701207

   Open questions at the time

   • The mechanism by which p37 controls p97 nuclear import or export is not defined
   • Whether p37 levels are altered in patient tissues with VCP mutations is unknown
   • Contribution of other p97 cofactors to nucleocytoplasmic shuttling has not been systematically compared

• The direct mechanism by which p37 controls p97 nucleocytoplasmic shuttling, the identity of p97/p37 substrates at centrosomes and the cortex, and the structural basis of p37 membrane recognition remain unresolved.
• No experimentally validated atomic structure of the p97–p37 complex exists
• Substrates extracted by p97/p37 at centrosomes and at the cell cortex are unidentified
• The nuclear import/export signal or carrier mediating p37-dependent p97 shuttling is unknown