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Ubx2 links the Cdc48 complex to ER-associated protein degradation.

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.

Pubmed ID: 16179953


  • Neuber O
  • Jarosch E
  • Volkwein C
  • Walter J
  • Sommer T


Nature cell biology

Publication Data

October 30, 2005

Associated Grants


Mesh Terms

  • Adenosine Triphosphatases
  • Carrier Proteins
  • Cell Cycle Proteins
  • Cell Membrane
  • Cytosol
  • Endoplasmic Reticulum
  • Proteasome Endopeptidase Complex
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Ubiquitin
  • Ubiquitin-Protein Ligases