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J. Biol. Chem., Vol. 280, Issue 29, 27339-27344, July 22, 2005

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Localization-independent Regulation of Homocysteine Secretion by Phosphatidylethanolamine N-Methyltransferase^*

David J. Shields, Susanne Lingrell, Luis B. Agellon, John T. Brosnan¶||, and Dennis E. Vance**

From the Department of Biochemistry and Canadian Institutes of Health Research Group on Molecular & Cell Biology of Lipids, University of Alberta, Edmonton, Alberta T6G 2S2, Canada and ^¶Department of Biochemistry, Memorial University of Newfoundland, St. John's, Newfoundland A1B 3X9, Canada

Genetic ablation of phosphatidylethanolamine N-methyltransferase (PEMT) in mice causes a 50% reduction in plasma homocysteine (Hcy) levels. Because hyperhomocysteinemia is an independent risk factor for cardiovascular disease, resolution of the molecular basis for this reduction is of significant clinical interest. The PEMT pathway is a metabolically channeled process localized to the endoplasmic reticulum (ER). To assess the importance of PEMT localization for Hcy homeostasis, we identified and ablated the minimal ER targeting motif. Mutagenesis of a conserved, C-terminal lysine residue (197) relocalized the enzyme to the Golgi, demonstrating that Lys-197 is essential for targeting PEMT to the ER. To evaluate the functional significance of PEMT localization, hepatoma cell lines were generated that stably expressed either ER- or Golgi-localized PEMT only. Intriguingly, stable expression of PEMT in either the ER or the Golgi caused increased Hcy secretion. Moreover, PEMT-mediated Hcy secretion correlated with the methyltransferase activity of the enzyme, independently of subcellular localization. Thus, our data suggest that Hcy homeostasis is regulated concomitantly with PEMT activity but independently of PEMT localization.

Received for publication, April 28, 2005 , and in revised form, May 27, 2005.

^* This research was supported in part by grants from the Canadian Institutes for Health Research (CIHR) and the Canadian Diabetes Association. 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.

Supported by a studentship from the Alberta Heritage Foundation for Medical Research. Current address: The Scripps Research Institute, 10550 N. Torrey Pines Rd. (IMM-24), La Jolla, CA 92037.

^|| CIHR Senior Investigator.

^** Canada Research Chair in Molecular and Cell Biology of Lipids and Heritage Medical Scientist of the Alberta Heritage Foundation for Medical Research. To whom correspondence should be addressed: 328 HMRC, Dept. of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2S2, Canada. Tel.: 780-492-8286; E-mail: Dennis.Vance{at}ualberta.ca.

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