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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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References

  1. Sommer, T. & Wolf, D. H. Endoplasmic reticulum degradation: reverse protein flow of no return. FASEB J. 11, 1227–1233 (1997).

    Article  CAS  Google Scholar 

  2. Kopito, R. R. ER quality control: the cytoplasmic connection. Cell 88, 427–430 (1997).

    Article  CAS  Google Scholar 

  3. Bonifacino, J. S. & Weissman, A. M. Ubiquitin and the control of protein fate in the secretory and endocytic pathways. Annu. Rev. Cell Dev. Biol. 14, 19– 57 (1998).

    Article  CAS  Google Scholar 

  4. Plemper, R. K. & Wolf, D. H. Retrograde protein translocation: ERADication of secretory proteins in health and disease. Trends Biochem. Sci. 24, 266–270 (1999).

    Article  CAS  Google Scholar 

  5. McCracken, A. A. & Brodsky, J. L. Assembly of ER-associated protein degradation in vitro: dependence on cytosol, calnexin, and ATP. J. Cell Biol. 132, 291–298 (1996).

    Article  CAS  Google Scholar 

  6. Plemper, R. K., Bohmler, S., Bordallo, J., Sommer, T. & Wolf, D. H. Mutant analysis links the translocon and BiP to retrograde protein transport for ER degradation. Nature 388, 891–895 ( 1997).

    Article  CAS  Google Scholar 

  7. Jakob, C. A., Burda, P., Roth, J. & Aebi, M. Degradation of misfolded endoplasmic reticulum glycoproteins in Saccharomyces cerevisiae is determined by a specific oligosaccharide structure. J. Cell Biol. 142, 1223–1233 (1998).

    Article  CAS  Google Scholar 

  8. Wiertz, E. J. et al.. Sec61-mediated transfer of a membrane protein from the endoplasmic reticulum to the proteasome for destruction. Nature 384, 432–438 (1996).

    Article  CAS  Google Scholar 

  9. Zhou, M. Y. & Schekman, R. The engagement of Sec61p in the ER dislocation process. Mol. Cell 4, 925 –934 (1999).

    Article  CAS  Google Scholar 

  10. Hampton, R. Y., Gardner, R. G. & Rine, J. Role of 26S proteasome and HRD genes in the degradation of 3-hydroxy-3-methylglutaryl-CoA reductase, an integral endoplasmic reticulum membrane protein. Mol. Biol. Cell 7, 2029 –2044 (1996).

    Article  CAS  Google Scholar 

  11. Knop, M., Finger, A., Braun, T., Hellmuth, K. & Wolf, D. H. Der1, a novel protein specifically required for endoplasmic reticulum degradation in yeast. EMBO J. 15, 753–763 (1996).

    Article  CAS  Google Scholar 

  12. Bordallo, J., Plemper, R. K., Finger, A. & Wolf, D. H. Der3p/Hrd1p is required for endoplasmic reticulum-associated degradation of misfolded lumenal and integral membrane proteins. Mol. Biol. Cell 9, 209–222 ( 1998).

    Article  CAS  Google Scholar 

  13. Deshaies, R. J. SCF and cullin/RING H2-based ubiquitin ligases. Annu. Rev. Cell Dev. Biol. 15, 435–467 ( 1999).

    Article  CAS  Google Scholar 

  14. Biederer, T., Volkwein, C. & Sommer, T. Degradation of subunits of the Sec61p complex, an integral component of the ER membrane, by the ubiquitin-proteasome pathway. EMBO J. 15, 2069–2076 ( 1996).

    Article  CAS  Google Scholar 

  15. Hiller, M. M., Finger, A., Schweiger, M. & Wolf, D. H. ER degradation of a misfolded luminal protein by the cytosolic ubiquitin-proteasome pathway. Science 273, 1725– 1728 (1996).

    Article  CAS  Google Scholar 

  16. Hampton, R. Y. & Bhakta, H. Ubiquitin-mediated regulation of 3-hydroxy-3-methylglutaryl-CoA reductase. Proc. Natl Acad. Sci. USA 94, 12944–12948 (1997).

    Article  CAS  Google Scholar 

  17. Biederer, T., Volkwein, C. & Sommer, T. Role of Cue1p in ubiquitination and degradation at the ER surface. Science 278, 1806– 1808 (1997).

    Article  CAS  Google Scholar 

  18. Chapman, R., Sidrauski, C. & Walter, P. Intracellular signaling from the endoplasmic reticulum to the nucleus. Annu. Rev. Cell Dev. Biol. 14, 459–485 (1998).

    Article  CAS  Google Scholar 

  19. Cox, J. S. & Walter, P. A novel mechanism for regulating activity of a transcription factor that controls the unfolded protein response . Cell 87, 391–404 (1996).

    Article  CAS  Google Scholar 

  20. Tirasophon, W., Welihinda, A. A. & Kaufman, R. J. A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells. Genes Dev. 12, 1812–1824 (1998).

    Article  CAS  Google Scholar 

  21. Sidrauski, C. & Walter, P. The transmembrane kinase Ire1p is a site-specific endonuclease that initiates mRNA splicing in the unfolded protein response. Cell 90, 1031– 1039 (1997).

    Article  CAS  Google Scholar 

  22. Kawahara, T., Yanagi, H., Yura, T. & Mori, K. Endoplasmic reticulum stress-induced mRNA splicing permits synthesis of transcription factor Hac1p/Ern4p that activates the unfolded protein response. Mol. Biol. Cell 8, 1845–1862 (1997).

    Article  CAS  Google Scholar 

  23. Seufert, W., McGrath, J. P. & Jentsch, S. UBC1 encodes a novel member of an essential subfamily of yeast ubiquitin-conjugating enzymes involved in protein degradation. EMBO J. 9, 4535–4541 ( 1990).

    Article  CAS  Google Scholar 

  24. Sommer, T. & Jentsch, S. A protein translocation defect linked to ubiquitin conjugation at the endoplasmic reticulum. Nature 365, 176–179 (1993).

    Article  CAS  Google Scholar 

  25. Jungmann, J., Reins, H-A., Schobert, C. & Jentsch, S. Resistance to cadmium mediated by ubiquitin-dependent proteolysis. Nature 361, 369–371 (1993).

    Article  CAS  Google Scholar 

  26. Kaufman, R. J. Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev. 13, 1211–1233 ( 1999).

    Article  CAS  Google Scholar 

  27. Seufert, W. & Jentsch, S. Ubiquitin-conjugating enzymes UBC4 and UBC5 mediate selective degradation of short-lived and abnormal proteins . EMBO J. 9, 543–550 (1990).

    Article  CAS  Google Scholar 

  28. Bush, K. T., Goldberg, A. L. & Nigam, S. K. Proteasome inhibition leads to a heat-shock response, induction of endoplasmatic reticulum chaperones, and thermotolerance. J. Biol. Chem. 272, 9086–9092 (1997).

    Article  CAS  Google Scholar 

  29. Ausubel, F. M. et al. Current Protocols in Molecular Biology (John Wiley and Sons, New York, 1989).

  30. Mori, K. et al. A 22 bp cis-acting element is necessary and sufficient for the induction of the yeast KAR2 (BiP) gene by unfolded proteins. EMBO J. 11, 2583–2593 ( 1992).

    Article  CAS  Google Scholar 

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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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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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