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A regulatory link between ER-associated protein degradation and the unfolded-protein response.

Nature Cell Biology volume 2, pages 379–384 (2000)Cite this article

Abstract

Ubiquitin conjugation during endoplasmic-reticulum-associated degradation (ERAD) depends on the activity of Ubc7. Here we show that Ubc1 acts as a further ubiquitin-conjugating enzyme in this pathway. Absence of both enzymes results in marked stabilization of an ERAD substrate and induction of the unfolded-protein response (UPR). Furthermore, basic ERAD activity is sufficient to eliminate unfolded proteins under normal conditions. However, when stress is applied, the UPR is required to increase ERAD activity. We thus demonstrate, for the first time, a regulatory loop between ERAD and the UPR, which is essential for normal growth of yeast cells.

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Figure 1: Degradation of CPY* is dependent on Ubc1 and Ubc7.
Figure 2: Hrd1 is epistatic to Ubc1 and Ubc7 with respect to CPY* degradation.
Figure 3: Disruption of ERAD causes induction of the UPR.
Figure 4: Degradation of misfolded proteins under normal growth conditions does not require the UPR.
Figure 5: Upregulation of ERAD components in response to dithiothreitol is dependent on an active UPR.
Figure 6: Mutations affecting ERAD and the UPR cause synthetic lethal phenotypes.
Figure 7: Δire1Δubc7 and Δire1Δ hrd1 double mutants are more sensitive to accumulation of unfolded proteins in the ER.

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Acknowledgements

We thank D. Wolf for the pRS306prc1–1 plasmid and the UPR– lacZ reporter construct, and K. Stade and members of the Sommer laboratory for helpful discussions and critical reading of the manuscript. This work was partially supported by grants from the Deutsche Forschungsgemeinschaft and the Deutsch-Israelische Projektkooperation (DIP) to T. S. E. J. was the recipient of fellowships from the Austrian Fonds zur Förderung der Wissenschaftlichen Forschungs and the Marie Curie TMR programme of the European Community.

Correspondence and request for materials should be addressed to T. S.

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  1. Ruth Friedlander and Ernst Jarosch: These authors contributed equally to this work

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  1. Max-Delbrück-Centrum für Molekulare Medizin, Robert-Rössle-Stra, e 10, Berlin, 13092, Germany

    Ruth Friedlander, Ernst Jarosch, Jörg Urban, Corinna Volkwein & Thomas Sommer

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Correspondence to Thomas Sommer.

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Friedlander, R., Jarosch, E., Urban, J. et al. A regulatory link between ER-associated protein degradation and the unfolded-protein response.. Nat Cell Biol 2, 379–384 (2000). https://doi.org/10.1038/35017001

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