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Vol. 19, Issue 10, 4506-4520, October 2008

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Genetic and Structural Analysis of Hmg2p-induced Endoplasmic Reticulum Remodeling in Saccharomyces cerevisiae

Christine M. Federovitch^*, Ying Z. Jones, Amy H. Tong, Charles Boone, William A. Prinz, and Randolph Y. Hampton^*

*UCSD Division of Biological Sciences, Section of Cell and Developmental Biology, University of California, San Diego, La Jolla, CA 92093-0347; National Center for Microscopy and Imaging Research, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093-0608; Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario, Canada M5G 1L6; and Laboratory of Cell Biochemistry and Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD 20892

Submitted December 5, 2007; Revised July 17, 2008; Accepted July 21, 2008
Monitoring Editor: Robert G. Parton

The endoplasmic reticulum (ER) is highly plastic, and increased expression of distinct single ER-resident membrane proteins, such as HMG-CoA reductase (HMGR), can induce a dramatic restructuring of ER membranes into highly organized arrays. Studies on the ER-remodeling behavior of the two yeast HMGR isozymes, Hmg1p and Hmg2p, suggest that they could be mechanistically distinct. We examined the features of Hmg2p required to generate its characteristic structures, and we found that the molecular requirements are similar to those of Hmg1p. However, the structures generated by Hmg1p and Hmg2p have distinct cell biological features determined by the transmembrane regions of the proteins. In parallel, we conducted a genetic screen to identify HER genes (required for Hmg2p-induced ER Remodeling), further confirming that the mechanisms of membrane reorganization by these two proteins are distinct because most of the HER genes were required for Hmg2p but not Hmg1p-induced ER remodeling. One of the HER genes identified was PSD1, which encodes the phospholipid biosynthetic enzyme phosphatidylserine decarboxylase. This direct connection to phospholipid biosynthesis prompted a more detailed examination of the effects of Hmg2p on phospholipid mutants and composition. Our analysis revealed that overexpression of Hmg2p caused significant and specific growth defects in nulls of the methylation pathway for phosphatidylcholine biosynthesis that includes the Psd1p enzyme. Furthermore, increased expression of Hmg2p altered the composition of cellular phospholipids in a manner that implied a role for PSD1. These phospholipid effects, unlike Hmg2p-induced ER remodeling, required the enzymatic activity of Hmg2p. Together, our results indicate that, although related, Hmg2p- and Hmg1p-induced ER remodeling are mechanistically distinct.

Address correspondence to: Randolph Y. Hampton (rhampton{at}ucsd.edu)

Abbreviations used: CD, cytoplasmic domain; EM, electron microscopy; ER, endoplasmic reticulum; HER, Hmg2p-induced ER remodeling; HMGR, Hmg-CoA reductase; hN, helical N; IF, immunofluorescence; P450, cytochrome P450; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PS, phosphatidylserine; TM, transmembrane.

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