期刊
FASEB JOURNAL
卷 24, 期 6, 页码 1914-1924出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.09-149765
关键词
HMG-CoA synthase 2; ketone bodies; mitochondria
资金
- Canadian Institutes of Health Research [MOP 81248]
- Heart and Stroke Foundation
- Province of Alberta graduate scholarship
- University of British Columbia's Child and Family Research Institute
- Canada Foundation for Innovation
- Michael Smith Foundation for Health Research
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 PPAR alpha 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/PPAR alpha 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 PPAR alpha and transcription at the Hmgcs2 PPRE. FASEB J. 24, 1914-1924 (2010). www.fasebj.org
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