Ubiquitins are zip codes for proteins heading to the proteasome. But misfolded ER proteins must be deubiquitinated before they are degraded, as shown by Wang et al. on page 963.
Misfolded ER proteins are sent back through the ER membrane into the cytosol by the p97 ATPase. Upon reaching the membrane's cytosolic side, the substrates are modified by ubiquitin ligases. Wang et al. found that an enzyme that undoes the work of the ligases, a deubiquitinase called ataxin-3 (atx3), associates with p97 and the rest of this ER-associated degradation (ERAD) complex.
Overexpression of an atx3 mutant that lacks its deubiquitinase activity blocked degradation of at least two ERAD substrates and thus induced ER stress. The mutant also led to an accumulation of ubiquitinated substrates that were bound to p97, suggesting that substrates must shed ubiquitins before they can be moved to the proteasome. As a few ubiquitins are needed to target proteins to the proteasome, atx3 probably trims, rather than removes, the ubiquitin chains.
The atx3 protein is also compromised by polyQ expansions that cause spinocerebellar ataxia. Preliminary data from Wang et al., as well as data from Zhong and Pittman (Hum. Mol. Genet. 2006. 15:2409), show that these mutations effectively block degradation of some ERAD substrates. The resulting ER stress likely leads to cell death and may be the cause of neurodegeneration.