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Science 323 (5922): 1693-1697

Copyright © 2009 by the American Association for the Advancement of Science

Comprehensive Characterization of Genes Required for Protein Folding in the Endoplasmic Reticulum

Martin C. Jonikas,1,2,3,4 Sean R. Collins,1,3,4 Vladimir Denic,1,3,4* Eugene Oh,1,3,4 Erin M. Quan,1,3,4 Volker Schmid,5 Jimena Weibezahn,1,3,4 Blanche Schwappach,5 Peter Walter,2,3 Jonathan S. Weissman,1,3,4{dagger} Maya Schuldiner1,3,4{ddagger}

Abstract: Protein folding in the endoplasmic reticulum is a complex process whose malfunction is implicated in disease and aging. By using the cell's endogenous sensor (the unfolded protein response), we identified several hundred yeast genes with roles in endoplasmic reticulum folding and systematically characterized their functional interdependencies by measuring unfolded protein response levels in double mutants. This strategy revealed multiple conserved factors critical for endoplasmic reticulum folding, including an intimate dependence on the later secretory pathway, a previously uncharacterized six-protein transmembrane complex, and a co-chaperone complex that delivers tail-anchored proteins to their membrane insertion machinery. The use of a quantitative reporter in a comprehensive screen followed by systematic analysis of genetic dependencies should be broadly applicable to functional dissection of complex cellular processes from yeast to human.

1 Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143, USA.
2 Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94143, USA.
3 Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
4 California Institute for Quantitative Biomedical Research, San Francisco, CA 94143, USA.
5 Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.

* Present address: Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.

{ddagger} Present address: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.

{dagger} To whom correspondence should be addressed. E-mail: weissman{at}cmp.ucsf.edu

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