TY - JOUR
T1 - A PGC-1α-O-GlcNAc transferase complex regulates FoxO transcription factor activity in response to glucose
AU - Housley, Michael P.
AU - Udeshi, Namrata D.
AU - Rodgers, Joseph T.
AU - Shabanowitz, Jeffrey
AU - Puigserver, Pere
AU - Hunt, Donald F.
AU - Hart, Gerald Warren
PY - 2009/2/20
Y1 - 2009/2/20
N2 - Metabolic and stress response gene regulation is crucial for the survival of an organism to a changing environment. Three key molecules that sense nutrients and broadly affect gene expression are the FoxO transcription factors, the transcriptional co-activator PGC-1α, and the dynamic post-translational modification, O-linked β-N-acetylglucosamine (O-GlcNAc). Here we identify novel post-translational modifications of PGC-1α, including O-GlcNAc, and describe a novel mechanism for how PGC-1α co-activates transcription by FoxOs. In liver, in cultured cells, and in vitro with recombinant proteins, PGC-1α binds to O-GlcNAc transferase and targets the enzyme to FoxOs, resulting in their increased GlcNAcylation and increased transcriptional activity. Furthermore, glucose-enhanced activation of FoxO1 occurs via this PGC-1α-O-GlcNAc transferase-mediated GlcNAcylation. Therefore, one mechanism by which PGC-1α can serve as a co-activator of transcription is by targeting the O-GlcNAc transferase to increase Glc-NAcylation of specific transcription factors important to nutrient/stress sensing and energy metabolism.
AB - Metabolic and stress response gene regulation is crucial for the survival of an organism to a changing environment. Three key molecules that sense nutrients and broadly affect gene expression are the FoxO transcription factors, the transcriptional co-activator PGC-1α, and the dynamic post-translational modification, O-linked β-N-acetylglucosamine (O-GlcNAc). Here we identify novel post-translational modifications of PGC-1α, including O-GlcNAc, and describe a novel mechanism for how PGC-1α co-activates transcription by FoxOs. In liver, in cultured cells, and in vitro with recombinant proteins, PGC-1α binds to O-GlcNAc transferase and targets the enzyme to FoxOs, resulting in their increased GlcNAcylation and increased transcriptional activity. Furthermore, glucose-enhanced activation of FoxO1 occurs via this PGC-1α-O-GlcNAc transferase-mediated GlcNAcylation. Therefore, one mechanism by which PGC-1α can serve as a co-activator of transcription is by targeting the O-GlcNAc transferase to increase Glc-NAcylation of specific transcription factors important to nutrient/stress sensing and energy metabolism.
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U2 - 10.1074/jbc.M808890200
DO - 10.1074/jbc.M808890200
M3 - Article
C2 - 19103600
AN - SCOPUS:64149111641
SN - 0021-9258
VL - 284
SP - 5148
EP - 5157
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 8
ER -