Nature Cell Biology
7, 993 - 998 (2005)
Published online: 18 September 2005; | doi:10.1038/ncb1298
Ubx2 links the Cdc48 complex to ER-associated protein degradationOliver Neuber1, Ernst Jarosch1, Corinna Volkwein1, Jan Walter1, 2
& Thomas Sommer11
Max-Delbrück Center for Molecular Medicine, Robert-Rössle Strasse 10, 13092 Berlin, Germany. 2
Present address: Sergievsky Center, Columbia University, 630 W 168th Street, New York, NY 10032, USA.
Correspondence should be addressed to Thomas Sommer tsommer@mdc-berlin.de Endoplasmic reticulum (ER)-associated protein degradation requires the dislocation of selected substrates from the ER to the cytosol for proteolysis via the ubiquitin−proteasome system. The AAA ATPase Cdc48 (known as p97 or VCP in mammals) has a crucial, but poorly understood role in this transport step. Here, we show that Ubx2 (Sel1) mediates interaction of the Cdc48 complex with the ER membrane-bound ubiquitin ligases Hrd1 (Der3) and Doa10. The membrane protein Ubx2 contains a UBX domain that interacts with Cdc48 and an additional UBA domain. Absence of Ubx2 abrogates breakdown of ER proteins but also that of a cytosolic protein, which is ubiquitinated by Doa10. Intriguingly, our results suggest that recruitment of Cdc48 by Ubx2 is essential for turnover of both ER and non-ER substrates, whereas the UBA domain of Ubx2 is specifically required for ER proteins only. Thus, a complex comprising the AAA ATPase, a ubiquitin ligase and the recruitment factor Ubx2 has a central role in ER-associated proteolysis.
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