Phosphatidylinositol 4-kinase IIIβ regulates the transport of ceramide between the endoplasmic reticulum and Golgi

Balázs Tóth, A. Balla, Hui Ma, Zachary A. Knight, Kevan M. Shokat, Tamas Balla

Research output: Contribution to journalArticle

102 Citations (Scopus)

Abstract

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 PI 3-kinase inhibitor, PIK93 that selectively inhibits the type III PI 4-kinase β enzyme, and small interfering RNA-mediated down-regulation of the individual PI 4-kinase enzymes, revealed that PI 4-kinase β has a dominant role in ceramide transport between the ER and Golgi. Accordingly, inhibition of PI 4-kinase III β either by wortmannin or PIK93 inhibited the conversion of [3H]serine-labeled endogenous ceramide to sphingomyelin. Therefore, PI 4-kinase β is a key enzyme in the control of spingomyelin synthesis by controlling the flow of ceramide from the ER to the Golgi compartment.

Original languageEnglish
Pages (from-to)36369-36377
Number of pages9
JournalJournal of Biological Chemistry
Volume281
Issue number47
DOIs
Publication statusPublished - Nov 24 2006

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1-Phosphatidylinositol 4-Kinase
Ceramides
Endoplasmic Reticulum
Enzymes
Phosphatidylinositol 3-Kinase
Sphingomyelins
Serine
Small Interfering RNA
Down-Regulation

ASJC Scopus subject areas

  • Biochemistry

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Phosphatidylinositol 4-kinase IIIβ regulates the transport of ceramide between the endoplasmic reticulum and Golgi. / Tóth, Balázs; Balla, A.; Ma, Hui; Knight, Zachary A.; Shokat, Kevan M.; Balla, Tamas.

In: Journal of Biological Chemistry, Vol. 281, No. 47, 24.11.2006, p. 36369-36377.

Research output: Contribution to journalArticle

Tóth, Balázs ; Balla, A. ; Ma, Hui ; Knight, Zachary A. ; Shokat, Kevan M. ; Balla, Tamas. / Phosphatidylinositol 4-kinase IIIβ regulates the transport of ceramide between the endoplasmic reticulum and Golgi. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 47. pp. 36369-36377.
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