A mitochondrial ketogenic enzyme regulates its gene expression by association with the nuclear hormone receptor PPARalpha.
Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mHMG-CoAS) is a key enzyme in ketogenesis, catalyzing the condensation of acetyl-CoA and acetoacetyl-CoA to generate HMG-CoA, which is eventually converted to ketone bodies. Transcription of the nuclear-encoded gene for mHMG-CoAS is stimulated by peroxisome proliferator-activated receptor (PPAR) alpha, a fatty acid-activated nuclear hormone receptor. Here we show that the mHMG-CoAS protein physically interacts with PPARalpha in vitro, and potentiates PPARalpha-dependent transcriptional activation via the cognate PPAR response element of the mHMG-CoAS gene in vivo. Immunofluorescence of transiently transfected cells demonstrated that in the presence of PPARalpha, mHMG-CoAS is translocated into the nucleus. Binding to PPARalpha, stimulation of PPARalpha activity and nuclear penetration require the integrity of the sequence LXXLL in mHMG-CoAS, a motif known to mediate the interaction between nuclear hormone receptors and coactivators. These findings reveal a novel mechanism of gene regulation whereby the product of a PPARalpha-responsive gene, normally resident in the mitochondria, directly interacts with this nuclear hormone receptor to autoregulate its own nuclear transcription.
Meertens
L M
LM
Department of Biochemistry, McMaster University, Hamilton, Ontario L8N 3Z5, Canada.
Miyata
K S
KS
Cechetto
J D
JD
Rachubinski
R A
RA
Capone
J P
JP
D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000235:genetics* / Q000378:metabolism*; D008928:Mitochondria / Q000201:enzymology*; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D021382:Protein Sorting Signals; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection
D009687:Nuclear Proteins; D021382:Protein Sorting Signals; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D006904:Hydroxymethylglutaryl-CoA Synthase