The AAA-ATPase VCP (also known as p97 or CDC48) uses ATP hydrolysis to ‘segregate’ ubiquitylated proteins from their binding partners, and has been implicated in numerous pathways ranging from ERAD to repair of damaged DNA. VCP acts through UBX-domain-containing adaptors that provide target specificity, but the targets and functions of UBXD proteins remain poorly understood. Through systematic proteomic analysis of UBXD proteins in human cells reported in Nature Cell Biology, the Harper lab revealed a network of over 195 interacting proteins, implicating VCP in diverse cellular pathways based on Gene Ontology analysis. Through detailed analysis of the interaction partners for the unstudied adaptor UBXN10, they uncover a role for this adaptor and VCP/p97 in ciliogenesis. UBXN10 associates with the intraflagellar transport B (IFT-B) complex, which regulates anterograde transport into cilia. Using TIRF microscopy in living cells, the demonstrate that UBXN10 is localized in cilia and traffics in cilia with the IFT-B complex. Moreover, deletion of UBXN10 using gene-editing renders cells unable to form cilia. Pharmacological inhibition of VCP destabilized they IFT-B complex and increased trafficking rates. Depletion of UBXN10 in zebrafish embryos causes defects in left–right asymmetry, which depends on functional cilia. This study provides a resource for exploring the landscape of UBXD proteins in biology and identifies an unexpected requirement for VCP–UBXN10 in ciliogenesis.
Raman, M, Sergeev, M, Garnaas M, Lydeard JR, Huttlin EL, Goessling W, Shah JV, and Harper JW. (2015) Systematic proteomics of the VCP–UBXD adaptor network identifies a role for UBXN10 in regulating ciliogenesis. Nature Cell Biology