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Eukaryotic Cell, April 2006, p. 712-722, Vol. 5, No. 4
1535-9778/06/$08.00+0     doi:10.1128/EC.5.4.712-722.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Endoplasmic Reticulum-Associated Degradation Is Required for Cold Adaptation and Regulation of Sterol Biosynthesis in the Yeast Saccharomyces cerevisiae

Jennifer Loertscher,¹ Lynnelle L. Larson,² Clinton K. Matson,³ Mark L. Parrish,⁴ Alicia Felthauser,³ Aaron Sturm,⁵ Christine Tachibana,⁶ Martin Bard,⁵ and Robin Wright^3*

Department of Chemistry, Seattle University, Seattle, Washington 98122,¹ Redmond High School, Redmond, Washington 98052,² Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota 55455,³ Department of Zoology, University of Washington, Seattle, Washington 98195,⁴ Department of Biology, Indiana University Purdue University Indianapolis, Indianapolis, Indiana 46202,⁵ Department of Biochemistry, University of Washington, Seattle, Washington 98195⁶

Received 15 September 2005/ Accepted 16 January 2006

Endoplasmic reticulum-associated degradation (ERAD) mediates the turnover of short-lived and misfolded proteins in the ER membrane or lumen. In spite of its important role, only subtle growth phenotypes have been associated with defects in ERAD. We have discovered that the ERAD proteins Ubc7 (Qri8), Cue1, and Doa10 (Ssm4) are required for growth of yeast that express high levels of the sterol biosynthetic enzyme, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR). Interestingly, the observed growth defect was exacerbated at low temperatures, producing an HMGR-dependent cold sensitivity. Yeast strains lacking UBC7, CUE1, or DOA10 also assembled aberrant karmellae (ordered arrays of membranes surrounding the nucleus that assemble when HMGR is expressed at high levels). However, rather than reflecting the accumulation of abnormal karmellae, the cold sensitivity of these ERAD mutants was due to increased HMGR catalytic activity. Mutations that compromise proteasomal function also resulted in cold-sensitive growth of yeast with elevated HMGR, suggesting that improper degradation of ERAD targets might be responsible for the observed cold-sensitive phenotype. However, the essential ERAD targets were not the yeast HMGR enzymes themselves. The sterol metabolite profile of ubc7 cells was altered relative to that of wild-type cells. Since sterol levels are known to regulate membrane fluidity, the viability of ERAD mutants expressing normal levels of HMGR was examined at low temperatures. Cells lacking UBC7, CUE1, or DOA10 were cold sensitive, suggesting that these ERAD proteins have a role in cold adaptation, perhaps through effects on sterol biosynthesis.

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* Corresponding author. Mailing address: Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN 55455. Phone: (612) 625-1183. Fax: (612) 626-6140. E-mail: wrightr{at}umn.edu.

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Eukaryotic Cell, April 2006, p. 712-722, Vol. 5, No. 4
1535-9778/06/$08.00+0     doi:10.1128/EC.5.4.712-722.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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