UBXD1 is a VCP-interacting protein that is involved in ER-associated degradation

AAA ATPase VCP and its yeast ortholog Cdc48. in a complex with the Ufd1-NpI4 heterodimer as an adaptor, play an essential role in endoplasmic reticulum-associated degradation (ERAD). Several UBX domain-containing proteins function to recruit ubiquitylated Substrates to VCP/Cdc48 by binding both VCP/Cdc48 and other ERAD components such as ubiquitin ligases. Here we show that mammalian UBXD1 is an additional UBX domain-containing protein involved in the ERAD process. UBXD1 is a cytosolic protein that interacts with VCP and Derlin-1. Overexpression of UBXD1 in cells Causes selective dissociation of Ufd1 from VCP, resulting in inhibition of mutant cystic fibrosis transmembrane conductance regulator (CFFR) degradation by ERAD. Additionally, depletion of endgenous UBXD1 protein by RNA interference also results in a defect in CFFR degradation. Collectively, these findings suggest that UBXD1 is a regulatory component of ERAD that may modulate the adaptor binding to VCP. (C) 2009 Elsevier Inc. All rights reserved.