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Ubx2 links the Cdc48 complex to ER-associated protein degradation

Nature Cell Biology volume 7, pages 993–998 (2005)Cite this article

Abstract

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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Figure 1: Turnover of the ERAD substrates CPY*, Sec61-2 and Ubc6 is impaired in the absence of Ubx2.
Figure 2: Ubx2 is an integral membrane protein exposing both the N- and C termini to the cytosol.
Figure 3: Ubx2 mediates interaction of the Cdc48 complex with the membrane-bound ubiquitin ligases Doa10 and Hrd1.
Figure 4: Δubx2 cells exhibit an induction of the unfolded protein response.
Figure 5: The N terminus of Ubx2 is crucial for breakdown of ERAD substrates but dispensable for the turnover of cytoplasmic or nuclear Deg1–GFP.

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Acknowledgements

The authors thank D. H. Wolf and T. A. Rapoport for the generous gift of strains and plasmids. We appreciate the helpful comments of the Sommer group on the manuscript. This work was partially supported by grants from the Deutsche Forschungs Gemeinschaft to T.S.

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  1. Jan Walter

    Present address: Sergievsky Center, Columbia University, 630 W 168th Street, New York, NY 10032, USA

Authors and Affiliations

  1. Max-Delbrück Center for Molecular Medicine, Robert-Rössle Strasse 10, Berlin, 13092, Germany

    Oliver Neuber, Ernst Jarosch, Corinna Volkwein, Jan Walter & Thomas Sommer

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Correspondence to Thomas Sommer.

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Neuber, O., Jarosch, E., Volkwein, C. et al. Ubx2 links the Cdc48 complex to ER-associated protein degradation. Nat Cell Biol 7, 993–998 (2005). https://doi.org/10.1038/ncb1298

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