title: Combinatorial regulation of a signal-dependent activator by phosphorylation and acetylation.
abstract: In the fasted state, increases in catecholamine signaling promote adipocyte function via the protein kinase A-mediated phosphorylation of cyclic AMP response element binding protein (CREB). CREB activity is further up-regulated in obesity, despite reductions in catecholamine signaling, where it contributes to the development of insulin resistance. Here we show that obesity promotes the CREB binding protein (CBP)-mediated acetylation of CREB at Lys136 in adipose. Under lean conditions, CREB acetylation was low due to an association with the energy-sensing NAD(+)-dependent deacetylase SirT1; amounts of acetylated CREB were increased in obesity, when SirT1 undergoes proteolytic degradation. Whereas CREB phosphorylation stimulated an association with the KIX domain of CBP, Lys136 acetylation triggered an interaction with the CBP bromodomain (BRD) that augmented recruitment of this coactivator to the promoter. Indeed, coincident Ser133 phosphorylation and Lys136 acetylation of CREB stimulated the formation of a ternary complex with the KIX and BRD domains of CBP by NMR analysis. As disruption of the CREB:BRD complex with a CBP-specific BRD inhibitor blocked effects of CREB acetylation on target gene expression, our results demonstrate how changes in nutrient status modulate cellular gene expression in response to hormonal signals.
authors.affiliation: Peptide Biology Laboratories, The Salk Institute for Biological Studies, La Jolla, CA 92037;
authors.forename: Jose C
authors.initials: JC
authors.lastname: Paz
authors.affiliation: Department of Integrative Structural and Computational Biology and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Sangho
authors.initials: S
authors.lastname: Park
authors.affiliation: Peptide Biology Laboratories, The Salk Institute for Biological Studies, La Jolla, CA 92037;
authors.forename: Naomi
authors.initials: N
authors.lastname: Phillips
authors.affiliation: Peptide Biology Laboratories, The Salk Institute for Biological Studies, La Jolla, CA 92037;
authors.forename: Shigenobu
authors.initials: S
authors.lastname: Matsumura
authors.affiliation: Peptide Biology Laboratories, The Salk Institute for Biological Studies, La Jolla, CA 92037;
authors.forename: Wen-Wei
authors.initials: WW
authors.lastname: Tsai
authors.affiliation: Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, TN 38105; and.
authors.forename: Lawryn
authors.initials: L
authors.lastname: Kasper
authors.affiliation: Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, TN 38105; and.
authors.forename: Paul K
authors.initials: PK
authors.lastname: Brindle
authors.affiliation: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Guangtao
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Zhou
authors.affiliation: Department of Integrative Structural and Computational Biology and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Peter E
authors.initials: PE
authors.lastname: Wright
authors.affiliation: Peptide Biology Laboratories, The Salk Institute for Biological Studies, La Jolla, CA 92037; montminy@salk.edu.
authors.forename: Marc
authors.initials: M
authors.lastname: Montminy
mesh_terms: D041721:3T3-L1 Cells; D000107:Acetylation; D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D009154:Mutation; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D050882:CREB-Binding Protein; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D008239:Lysine
keywords: CBP; CREB; SirT1; acetylation; phosphorylation