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J. Biol. Chem., Vol. 281, Issue 47, 36369-36377, November 24, 2006

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Phosphatidylinositol 4-Kinase III Regulates the Transport of Ceramide between the Endoplasmic Reticulum and Golgi^*

Balázs Tóth, András Balla, Hui Ma, Zachary A. Knight¹, Kevan M. Shokat^¶1, and Tamas Balla²

From the Section on Molecular Signal Transduction, NICHD, National Institutes of Health, Bethesda, Maryland 20892 and the Program in Chemistry and Chemical Biology, University of California, ^¶Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California 94143

The recently identified ceramide transfer protein, CERT, is responsible for the bulk of ceramide transport from the endoplasmic reticulum (ER) to the Golgi. CERT has a C-terminal START domain for ceramide binding and an N-terminal pleck-strin homology domain that binds phosphatidylinositol 4-phosphate suggesting that phosphatidylinositol (PI) 4-kinases are involved in the regulation of CERT-mediated ceramide transport. In the present study fluorescent analogues were used to follow the ER to Golgi transport of ceramide to determine which of the four mammalian PI 4-kinases are involved in this process. Overexpression of pleckstrin homology domains that bind phosphatidylinositol 4-phosphate strongly inhibited the transport of C5-BODIPY-ceramide to the Golgi. A newly identified PI 3-kinase inhibitor, PIK93 that selectively inhibits the type III PI 4-kinase enzyme, and small interfering RNA-mediated down-regulation of the individual PI 4-kinase enzymes, revealed that PI 4-kinase has a dominant role in ceramide transport between the ER and Golgi. Accordingly, inhibition of PI 4-kinase III either by wortmannin or PIK93 inhibited the conversion of [³H]serine-labeled endogenous ceramide to sphingomyelin. Therefore, PI 4-kinase is a key enzyme in the control of spingomyelin synthesis by controlling the flow of ceramide from the ER to the Golgi compartment.

Received for publication, May 23, 2006 , and in revised form, September 12, 2006.

^* This work was supported in part a grant from the Intramural Research Program of the NICHD, National Institutes of Health (to B. T., A. B., H. M., and T. B.). 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.

¹ Supported by National Institutes of Health Grant AI-44009.

² To whom correspondence should be addressed: Bldg. 49, Rm. 6A35, 49 Convent Dr., Bethesda, MD 20892-4510. Tel.: 301-496-2136; Fax: 301-480-8010; E-mail: ballat{at}mail.nih.gov.

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