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Palmitoylation of ketogenic enzyme HMGCS2 enhances its interaction with PPARα and transcription at the Hmgcs2 PPRE
Author(s) -
Kostiuk Morris A.,
Keller Bernd O.,
Berthiaume Luc G.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.09-149765
Subject(s) - transcription factor , palmitoylation , transcription (linguistics) , chemistry , enzyme , microbiology and biotechnology , ketogenic diet , biology , biochemistry , gene , neuroscience , linguistics , philosophy , cysteine , epilepsy
Excessive liver production of ketone bodies is one of many metabolic complications that can arise from diabetes, and in severe untreated cases, it can result in ketoacidosis, coma, and death. Mitochondrial HMG‐CoA synthase (HMGCS2), the rate‐limiting enzyme in ketogenesis, has been shown to interact with PPARα and act as a coactivator to up‐regulate transcription from the PPRE of its own gene. Although protein palmitoylation is typically a cytosolic process that promotes membrane association, we recently identified 21 palmitoylated proteins in rat liver mitochondria, including HMGCS2. Herein, our data support a mechanism whereby palmitate is first added onto HMGCS2 active site Cys166 and then transacylated to Cys305. Palmitoylation promotes the HMGCS2/PPARα interaction, resulting in transcriptional activation from the Hmgcs2 PPRE. These results, together with the fact that 8 of the 21 palmitoylated mitochondrial proteins that we previously identified have nuclear receptor interacting motifs, demonstrate a novel—and perhaps ubiquitous—role for palmitoylation as a modulator of transcription.—Kostiuk, M. A., Keller, B. O., Berthiaume, L. G. Palmitoylation of ketogenic enzyme HMGCS2 enhances its interaction with PPARα and transcription at the Hmgcs2 PPRE. FASEB J. 24, 1914–1924 (2010). www.fasebj.org