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A complex of Yos9p and the HRD ligase integrates endoplasmic reticulum quality control into the degradation machinery

Nature Cell Biology volume 8, pages 849–854 (2006)Cite this article

Abstract

A quality-control system surveys the lumen of the endoplasmic reticulum for terminally misfolded proteins. Polypeptides singled out by this system are ultimately degraded by the cytosolic ubiquitin-proteasome pathway. Key components of both the endoplasmic reticulum quality-control system and the degradation machinery have been identified, but a connection between the two systems has remained elusive. Here, we report an association between the endoplasmic reticulum quality-control lectin Yos9p and Hrd3p, a component of the ubiquitin-proteasome system that links these pathways. We identify designated regions in the luminal domain of Hrd3p that interact with Yos9p and the ubiquitin ligase Hrd1p. Binding of misfolded proteins occurs through Hrd3p, suggesting that Hrd3p recognises proteins that deviate from their native conformation, whereas Yos9p ensures that only terminally misfolded polypeptides are degraded.

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Figure 1: Yos9p is a component of the HRD ligase.
Figure 2: Yos9p is an integral subunit of the HRD ligase.
Figure 3: The endoplasmic reticulum luminal domain of Hrd3p comprises distinct binding regions for Hrd1p and Yos9p.
Figure 4: Yos9p binds Hrd3p through a region adjacent to its MRH domain.
Figure 5: Recruitment of CPY* to the HRD ligase occurs independently of Yos9p.

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Acknowledgements

We thank C. Volkwein and A. Wittstruck for excellent technical assistance and D. H. Wolf for providing plasmids and reagents. Part of this work was supported by grants from the Deutsche Forschungsgemeinschaft (DFG) and the EU Network of Excellence RUBICON. R.G. thanks the Boehringer Ingelheim Fonds for support.

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  1. Max-Delbrück Center for Molecular Medicine, Robert-Rössle-Str. 10, Berlin, 13125, Germany

    Robert Gauss, Ernst Jarosch, Thomas Sommer & Christian Hirsch

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  1. Robert Gauss
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  2. Ernst Jarosch
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Contributions

The experimental concept was developed by C.H., R.G. and E.J. T.S. guided the project planning. R.G. performed all experiments except Fig. 1c and d (E.J.) and Fig. 5b (C.H.). C.H. wrote the manuscript.

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Correspondence to Thomas Sommer.

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The authors declare no competing financial interests.

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Supplementary Figures S1, S2 and S3 (PDF 143 kb)

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Gauss, R., Jarosch, E., Sommer, T. et al. A complex of Yos9p and the HRD ligase integrates endoplasmic reticulum quality control into the degradation machinery. Nat Cell Biol 8, 849–854 (2006). https://doi.org/10.1038/ncb1445

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