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J. Biol. Chem., Vol. 283, Issue 49, 34204-34217, December 5, 2008

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Cell Wall Integrity MAPK Pathway Is Essential for Lipid Homeostasis^*

Lilia R. Nunez¹, Stephen A. Jesch¹, Maria L. Gaspar, Claudia Almaguer, Manuel Villa-Garcia, Monica Ruiz-Noriega^¶, Jana Patton-Vogt, and Susan A. Henry²

From the Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853, the Department of Biological Sciences, Duquesne University, Pittsburgh, Pennsylvania 15282, and the ^¶Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213

The highly conserved yeast cell wall integrity mitogen-activated protein kinase pathway regulates cellular responses to cell wall and membrane stress. We report that this pathway is activated and essential for viability under growth conditions that alter both the abundance and pattern of synthesis and turnover of membrane phospholipids, particularly phosphatidylinositol and phosphatidylcholine. Mutants defective in this pathway exhibit a choline-sensitive inositol auxotrophy, yet fully derepress INO1 and other Opi1p-regulated genes when grown in the absence of inositol. Under these growth conditions, Mpk1p is transiently activated by phosphorylation and stimulates the transcription of known targets of Mpk1p signaling, including genes regulated by the Rlm1p transcription factor. mpk1 cells also exhibit severe defects in lipid metabolism, including an abnormal accumulation of phosphatidylcholine, diacylglycerol, triacylglycerol, and free sterols, as well as aberrant turnover of phosphatidylcholine. Overexpression of the NTE1 phospholipase B gene suppresses the choline-sensitive inositol auxotrophy of mpk1 cells, whereas overexpression of other phospholipase genes has no effect on this phenotype. These results indicate that an intact cell wall integrity pathway is required for maintaining proper lipid homeostasis in yeast, especially when cells are grown in the absence of inositol.

Received for publication, August 18, 2008 , and in revised form, October 2, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants GM019629 (to S. A. H.) and GM59817 (to J. P.-V.). This study is taken in part from the Ph.D. thesis of L. R. N., published under the name Lilia Nunez-Rodriguez (Cornell University, 2006). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Molecular Biology and Genetics, 260 Roberts Hall, Cornell University, Ithaca, NY 14853-5905. Tel.: 607-255-2241; Fax: 607-255-3803; E-mail: sah42{at}cornell.edu.

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