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

doi:10.1128/EC.5.4.712-722.2006

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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 Wright³^*

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) mediatesthe turnover of short-lived and misfolded proteins in the ERmembrane or lumen. In spite of its important role, only subtlegrowth 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 expresshigh levels of the sterol biosynthetic enzyme, 3-hydroxy-3-methylglutarylcoenzyme A reductase (HMGR). Interestingly, the observed growthdefect was exacerbated at low temperatures, producing an HMGR-dependentcold sensitivity. Yeast strains lacking UBC7, CUE1, or DOA10also assembled aberrant karmellae (ordered arrays of membranessurrounding the nucleus that assemble when HMGR is expressedat high levels). However, rather than reflecting the accumulationof abnormal karmellae, the cold sensitivity of these ERAD mutantswas due to increased HMGR catalytic activity. Mutations thatcompromise proteasomal function also resulted in cold-sensitivegrowth of yeast with elevated HMGR, suggesting that improperdegradation of ERAD targets might be responsible for the observedcold-sensitive phenotype. However, the essential ERAD targetswere not the yeast HMGR enzymes themselves. The sterol metaboliteprofile of ubc7 ${Delta}$ cells was altered relative to that of wild-typecells. Since sterol levels are known to regulate membrane fluidity,the viability of ERAD mutants expressing normal levels of HMGRwas examined at low temperatures. Cells lacking UBC7, CUE1,or DOA10 were cold sensitive, suggesting that these ERAD proteinshave a role in cold adaptation, perhaps through effects on sterolbiosynthesis.

* 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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