Ataxin-3 (ATXN3) binds Valosin-containing protein (VCP) (Dos-Pepe et al. 2003), a 26S proteasome-associated multiubiquitin chain-targeting factor required for protein degradation by the ubiquitin-proteasome pathway (Dai & Li 2001). One of the functions of VCP is the regulation of misfolded endoplasmic reticulum (ER) proteins a process named ER-associated degradation (ERAD) (Zhong & Pittman 2006, Liu & Ye 2012). VCP increases the ubiquitinase activity of ATXN3 (Laco et al. 2012) and may act as an 'uncoupling factor' that transfers ubiquitinated substrates from RAD23 to ATXN3 (Doss-Pepe et al. 2003). In this model multiubiquitinated proteolytic substrates bind to RAD23 through its UBA domains, while VCP associates with ATXN3 at the proteasome. RAD23 plus substrate would bind to the proteasome (conceivably an ataxin-3-containing proteasome) via its UbL domain. VCP would transfer multiubiquitinated substrates from RAD23 to ATXN3 (Doss-Pepe et al. 2003). VCP is found as a component of abnormal protein aggregates (Hirabayashi et al. 2001) and has been identified as a modulator of polyglutamine-induced neurodegeneration (Higashiyama et al. 2002). Mutant ATXN3 with an expanded polyQ tract binds VCP more efficiently than wild-type ATXN3, interfering with the degradation of ubiquitinated substrates (Laco et al. 2012).