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Published online 24 July 2006. doi:10.1083/jcb.200601051
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 174, Number 3, 369-377
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Article

Identification of Golgi-localized acyl transferases that palmitoylate and regulate endothelial nitric oxide synthase



Carlos Fernández-Hernando1, Masaki Fukata2,3, Pascal N. Bernatchez1, Yuko Fukata2, Michelle I. Lin1, David S. Bredt4, and William C. Sessa1

1 Department of Pharmacology and Program in Vascular Cell Signaling and Therapeutics, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, CT 06536
2 Laboratory of Genomics and Proteomics, National Institute for Longevity Sciences, Aichi 474-8522, Japan
3 Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan
4 Department of Integrative Biology, Eli Lilly and Company, Indianapolis, IN 46285

Correspondence to William C. Sessa: william.sessa{at}yale.edu

Lipid modifications mediate the subcellular localization and biological activity of many proteins, including endothelial nitric oxide synthase (eNOS). This enzyme resides on the cytoplasmic aspect of the Golgi apparatus and in caveolae and is dually acylated by both N-myristoylation and S-palmitoylation. Palmitoylation-deficient mutants of eNOS release less nitric oxide (NO). We identify enzymes that palmitoylate eNOS in vivo. Transfection of human embryonic kidney 293 cells with the complementary DNA (cDNA) for eNOS and 23 cDNA clones encoding the Asp-His-His-Cys motif (DHHC) palmitoyl transferase family members showed that five clones (2, 3, 7, 8, and 21) enhanced incorporation of [3H]-palmitate into eNOS. Human endothelial cells express all five of these enzymes, which colocalize with eNOS in the Golgi and plasma membrane and interact with eNOS. Importantly, inhibition of DHHC-21 palmitoyl transferase, but not DHHC-3, in human endothelial cells reduces eNOS palmitoylation, eNOS targeting, and stimulated NO production. Collectively, our data describe five new Golgi-targeted DHHC enzymes in human endothelial cells and suggest a regulatory role of DHHC-21 in governing eNOS localization and function.

Abbreviations used in this article: CRD, cysteine-rich domain; eNOS, endothelial NO synthase; HEK, human embryonic kidney; HUVEC, human umbilical vein endothelial cell; NO, nitric oxide; PAT, palmitoyl acyl transferase; WT, wild-type.


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