Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 281, Issue 47, Pages 36369-36377Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M604935200
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- Intramural NIH HHS Funding Source: Medline
- NIAID NIH HHS [AI044009] Funding Source: Medline
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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 pleckstrin 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 PI3-kinase inhibitor, PIK93 that selectively inhibits the type III PI4-kinase beta enzyme, and small interfering RNA-mediated down-regulation of the individual PI4-kinase enzymes, revealed that PI4-kinase beta has a dominant role in ceramide transport between the ER and Golgi. Accordingly, inhibition of PI4-kinase III beta either by wortmannin or PIK93 inhibited the conversion of [H-3] serine-labeled endogenous ceramide to sphingomyelin. Therefore, PI4-kinase beta is a key enzyme in the control of spingomyelin synthesis by controlling the flow of ceramide from the ER to the Golgi compartment.
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