SUMOylation Attenuates the Function of PGC-1α

Peroxisome proliferator-activated receptor γ-coactivator-1α (PGC-1α) is a key coordinator of gene programs in metabolism and energy homeostasis in mammals. It is highly responsive to changes in the cellular environment and physiological status of mammals and regulated by post-translational modifications: acetylation, phosphorylation, and methylation. Here, we show that PGC-1α is covalently modified by small ubiquitin-like modifier (SUMO) 1 protein, an important regulator of signaling and transcription. Conserved lysine residue 183 located in the activation domain of PGC-1α was identified as the major site of SUMO conjugation. Interestingly, the same Lys residue is also a target for acetylation. Therefore, the E185A mutation disrupting the SUMOylation consensus sequence was utilized to show that SUMOylation plays a role in the regulation of PGC-1α function. Our results show that SUMOylation does not have an apparent effect on the subcellular localization or the stability of PGC-1α, but it attenuates the transcriptional activity of the coactivator, probably by enhancing the interaction of PGC-1α with corepressor RIP140. Mutation that abolished the SUMOylation augments the activity of PGC-1α also in the context of PPARγ-dependent transcription. Thus, our findings showing that reversible SUMOylation can adjust the activity of PGC-1α add a novel layer to the regulation of the coactivator. Peroxisome proliferator-activated receptor γ-coactivator-1α (PGC-1α) is a key coordinator of gene programs in metabolism and energy homeostasis in mammals. It is highly responsive to changes in the cellular environment and physiological status of mammals and regulated by post-translational modifications: acetylation, phosphorylation, and methylation. Here, we show that PGC-1α is covalently modified by small ubiquitin-like modifier (SUMO) 1 protein, an important regulator of signaling and transcription. Conserved lysine residue 183 located in the activation domain of PGC-1α was identified as the major site of SUMO conjugation. Interestingly, the same Lys residue is also a target for acetylation. Therefore, the E185A mutation disrupting the SUMOylation consensus sequence was utilized to show that SUMOylation plays a role in the regulation of PGC-1α function. Our results show that SUMOylation does not have an apparent effect on the subcellular localization or the stability of PGC-1α, but it attenuates the transcriptional activity of the coactivator, probably by enhancing the interaction of PGC-1α with corepressor RIP140. Mutation that abolished the SUMOylation augments the activity of PGC-1α also in the context of PPARγ-dependent transcription. Thus, our findings showing that reversible SUMOylation can adjust the activity of PGC-1α add a novel layer to the regulation of the coactivator. The transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator-1α (or PPARGC1α or PGC-1α) 2The abbreviations used are: PGCperoxisome proliferator-activated receptor γ coactivatorPPARγperoxisome proliferator-activated receptor γSUMOsmall ubiquitin-like modifierMAPKmitogen-activated protein kinasePIASprotein inhibitor of activated signal transducers and activators of transcriptionSENPSUMO-specific proteaseNAMnicotinamideRIP140receptor-interacting protein 140AMPKAMP-activated protein kinaseE1ubiquitin-activating enzymeE2ubiquitin carrier proteinE3ubiquitin-protein isopeptide ligasePICprotease inhibitor mixtureNEMN-ethylmaleimideHAhemagglutininGSTglutathione S-transferaseERRestrogen receptor-related receptor. 2The abbreviations used are: PGCperoxisome proliferator-activated receptor γ coactivatorPPARγperoxisome proliferator-activated receptor γSUMOsmall ubiquitin-like modifierMAPKmitogen-activated protein kinasePIASprotein inhibitor of activated signal transducers and activators of transcriptionSENPSUMO-specific proteaseNAMnicotinamideRIP140receptor-interacting protein 140AMPKAMP-activated protein kinaseE1ubiquitin-activating enzymeE2ubiquitin carrier proteinE3ubiquitin-protein isopeptide ligasePICprotease inhibitor mixtureNEMN-ethylmaleimideHAhemagglutininGSTglutathione S-transferaseERRestrogen receptor-related receptor. was first isolated from brown fat (1Puigserver P. Wu Z. Park C.W. Graves R. Wright M. Spiegelman B.M. Cell. 1998; 92: 829-839Abstract Full Text Full Text PDF PubMed Scopus (3030) Google Scholar). It was found to be important in the regulation of mitochondrial function and metabolism. Although the PGC-1α was initially named according to its function as a coactivator for PPARγ, it is also able to interact via its N-terminal LXXLL motifs and coactivate with several other nuclear receptors, including estrogen receptor α, thyroid hormone receptor β, and glucocorticoid receptor, as well as other transcription factors, such as FoxO1 (2Tcherepanova I. Puigserver P. Norris J.D. Spiegelman B.M. McDonnell D.P. J. Biol. Chem. 2000; 275: 16302-16308Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar, 3Knutti D. Kaul A. Kralli A. Mol. Cell. Biol. 2000; 20: 2411-2422Crossref PubMed Scopus (240) Google Scholar, 4Puigserver P. Rhee J. Donovan J. Walkey C.J. Yoon J.C. Oriente F. Kitamura Y. Altomonte J. Dong H. Accili D. Spiegelman B.M. Nature. 2003; 423: 550-555Crossref PubMed Scopus (1154) Google Scholar, 5Puigserver P. Spiegelman B.M. Endocr. Rev. 2003; 24: 78-90Crossref PubMed Scopus (1590) Google Scholar, 6Lin J. Handschin C. Spiegelman B.M. Cell. Metab. 2005; 1: 361-370Abstract Full Text Full Text PDF PubMed Scopus (1634) Google Scholar, 7Rodgers J.T. Lerin C. Gerhart-Hines Z. Puigserver P. FEBS Lett. 2008; 582: 46-53Crossref PubMed Scopus (490) Google Scholar). PGC-1α is regulated by several signaling pathways and post-translational modifications (7Rodgers J.T. Lerin C. Gerhart-Hines Z. Puigserver P. FEBS Lett. 2008; 582: 46-53Crossref PubMed Scopus (490) Google Scholar). Protein arginine methyltransferase PRMT1 potentiates the coactivator function of PGC-1α by methylating three C-terminal amino acid residues Arg665, Arg667, and Arg669 within its RNA-binding domain (8Teyssier C. Ma H. Emter R. Kralli A. Stallcup M.R. Genes Dev. 2005; 19: 1466-1473Crossref PubMed Scopus (190) Google Scholar). Distinct protein kinases exert complex regulation via targeting several sites in PGC-1α. Phosphorylation of Thr177 and Ser538 by AMP-activated protein kinase (AMPK) augments the coactivation function of PGC-1α (9Jager S. Handschin C. St-Pierre J. Spiegelman B.M. Proc. Natl. Acad. Sci. U.S.A. 2007; 104: 12017-12022Crossref PubMed Scopus (1749) Google Scholar), whereas protein kinase kinase of can PGC-1α Nature. 2007; PubMed Scopus Google Scholar). Phosphorylation of PGC-1α amino acid residues and by in to activation of the PGC-1α, in via the of protein from PGC-1α P. Rhee J. J. Wu Z. Yoon J.C. S. Spiegelman B.M. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, M. Rhee J. St-Pierre J. Handschin C. Puigserver P. J. S. H. P. Spiegelman B.M. Genes Dev. PubMed Scopus Google Scholar). Interestingly, the sites with by kinase can target the protein for and S. Kralli A. Genes Dev. 2008; PubMed Scopus Google Scholar). PGC-1α several lysine the protein J.T. Lerin C. Spiegelman B.M. Puigserver P. Nature. 2005; PubMed Scopus Google Scholar). of amino acid PGC-1α, its coactivator activity Puigserver Full Text Full Text PDF PubMed Scopus Google Scholar). The be to of PGC-1α to it with transcriptional such as RIP140. activity of can PGC-1α in an and to J.T. Lerin C. Spiegelman B.M. Puigserver P. Nature. 2005; PubMed Scopus Google Scholar, S. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google to and lysine residues can be covalently modified by and ubiquitin-like three small ubiquitin-like modifier (SUMO) and that of amino and can isopeptide with of is with whereas and D. H. 2007; PubMed Scopus Google Scholar, F. Cell. 1: PubMed Scopus Google Scholar). Although and a amino acid and to the of lysine is found within a consensus is a and is M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). is not to whereas and can The SUMO is to that of but and for first activated in an by the and and by and protein able to SUMOylation in a that the of F. M. A. Sci. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). SUMOylation is not a but is by and The can be by a of Biol. 2007; Full Text Full Text PDF PubMed Scopus Google as a in in transcription and signal the can in a the subcellular and localization of the protein, its to interact with other its activity in transcription in F. Cell. 1: PubMed Scopus Google and P. Biol. 2007; 19: PubMed Scopus Google Scholar). the same lysine residue can be by or the can a protein from of SUMO can interact with in and J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, A. Biol. 2008; PubMed Scopus Google Scholar). to targeting a of transcription factors, SUMOylation to transcriptional such as and and such as and D. D. A. Mol. Cell. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, H. Y. Y. R. Y. J. D. Wu D. S. Y. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, A. M. A. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J. M. M. F. Mol. Biol. Cell. PubMed Scopus Google Scholar, J. Biol. Chem. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). Here, we show that reversible SUMOylation can the transcriptional activity of PGC-1α an apparent effect on its we have of the transcriptional coactivator PGC-1α and show that the lysine residue 183 that is located in the transcription activation domain of PGC-1α is to reversible The lysine to the SUMO consensus and the site is from to The coactivator PGC-1α also that the but the site was not to by Interestingly, is also the residues in PGC-1α that by PGC-1α an site to to a to the effect of J.T. Lerin C. Spiegelman B.M. Puigserver P. Nature. 2005; PubMed Scopus Google Scholar). have not the role of for the function of the coactivator. Interestingly, mutation of to and a enhancing effect on the transcriptional activity of PGC-1α. Mutation of the residue the in the SUMOylation consensus SUMOylation but is to and also and to the role of SUMOylation from the other lysine modifications in the PGC-1α function. Interestingly, the E185A was also the coactivator. the context of isolated N-terminal activation the E185A transcriptional activity the with of the activation of the SUMOylation consensus of PGC-1α its as a coactivator for and transcription. the coactivator activity in the context of nuclear receptors, results that and SUMOylation have in the regulation of PGC-1α function in the nuclear receptor we the that the of the SUMOylation consensus the of It is also that is by other lysine such as and and be a or a lysine Although was the major sites and the SUMOylation site of PGC-1α, signaling was able to the SUMOylation of PGC-1α. via of the SUMOylation N-terminal domain of PGC-1α motifs M. S. C. J. S. M. S. F. H. J. Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar), the C-terminal of with of the S. Kralli A. Genes Dev. 2008; PubMed Scopus Google Scholar). The SUMOylation site of PGC-1α the but our not in the stability or of the PGC-1α with the of with inhibitor results in of PGC-1α protein and of of PGC-1α M. S. C. J. S. M. S. F. H. J. Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). a in but the effect of the inhibitor on the not the and the PGC-1α Our that PGC-1α the of in small in the is in with the Puigserver Full Text Full Text PDF PubMed Scopus Google Scholar, M. S. C. J. S. M. S. F. H. J. Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). of the SUMOylation site of PGC-1α not the nuclear of in the same lysine residue can be by or SUMOylation transcription and Cell. 2005; PubMed Scopus Google Scholar, Mol. Cell. Biol. 2005; PubMed Scopus Google Scholar, S. J. S. C. A. D. Mol. Cell. Biol. 2007; PubMed Scopus Google Scholar). the of in is an the of modifications in that the activation of that results in SUMOylation of the same lysine residue S. J. S. C. A. D. Mol. Cell. Biol. 2007; PubMed Scopus Google Scholar). and SUMOylation was not with PGC-1α, of the activity by not show apparent effect on the SUMOylation of including and to interact with the N-terminal activation domain of PGC-1α (7Rodgers J.T. Lerin C. Gerhart-Hines Z. Puigserver P. FEBS Lett. 2008; 582: 46-53Crossref PubMed Scopus (490) Google Scholar, P. Wu Z. M. J. Spiegelman B.M. PubMed Scopus Google Scholar). SUMO is a the effect of the SUMOylation be to the that the from with the activation we not the PGC-1α and its SUMOylation with to to and in our transcription the other SUMOylation of PGC-1α with such as to PGC-1α and with it in the same Puigserver Full Text Full Text PDF PubMed Scopus Google Scholar, M. Kralli A. R. M. Mol. Cell. Biol. 2008; PubMed Google Scholar). of the corepressor we found that of the SUMOylation consensus E185A the transcription activation function of PGC-1α to the by RIP140. our that the can a role in and of to the Interestingly, is also covalently modified by J. Biol. Chem. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar), but its SUMOylation does not to a role in the of and with Puigserver Full Text Full Text PDF PubMed Scopus Google Scholar). to our and but not the for the SUMOylation of PGC-1α. be in the regulation of PGC-1α protein and SUMOylation of such as transcription β, is a corepressor regulated by SUMOylation and is also found in complex with PGC-1α Puigserver Full Text Full Text PDF PubMed Scopus Google Scholar, D. P. P. M. J. Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google our that the N-terminal domain of PGC-1α is to reversible SUMO that its to function as a transcriptional coactivator a novel to the regulation of the PGC-1α The SUMOylation as a to PGC-1α activity cellular activity the The transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator-1α (or PPARGC1α or PGC-1α) 2The abbreviations used are: PGCperoxisome proliferator-activated receptor γ coactivatorPPARγperoxisome proliferator-activated receptor γSUMOsmall ubiquitin-like modifierMAPKmitogen-activated protein kinasePIASprotein inhibitor of activated signal transducers and activators of transcriptionSENPSUMO-specific proteaseNAMnicotinamideRIP140receptor-interacting protein 140AMPKAMP-activated protein kinaseE1ubiquitin-activating enzymeE2ubiquitin carrier proteinE3ubiquitin-protein isopeptide ligasePICprotease inhibitor mixtureNEMN-ethylmaleimideHAhemagglutininGSTglutathione S-transferaseERRestrogen receptor-related receptor. 2The abbreviations used are: PGCperoxisome proliferator-activated receptor γ coactivatorPPARγperoxisome proliferator-activated receptor γSUMOsmall ubiquitin-like modifierMAPKmitogen-activated protein kinasePIASprotein inhibitor of activated signal transducers and activators of transcriptionSENPSUMO-specific proteaseNAMnicotinamideRIP140receptor-interacting protein 140AMPKAMP-activated protein kinaseE1ubiquitin-activating enzymeE2ubiquitin carrier proteinE3ubiquitin-protein isopeptide ligasePICprotease inhibitor mixtureNEMN-ethylmaleimideHAhemagglutininGSTglutathione S-transferaseERRestrogen receptor-related receptor. was first isolated from brown fat (1Puigserver P. Wu Z. Park C.W. Graves R. Wright M. Spiegelman B.M. Cell. 1998; 92: 829-839Abstract Full Text Full Text PDF PubMed Scopus (3030) Google Scholar). It was found to be important in the regulation of mitochondrial function and metabolism. Although the PGC-1α was initially named according to its function as a coactivator for PPARγ, it is also able to interact via its N-terminal LXXLL motifs and coactivate with several other nuclear receptors, including estrogen receptor α, thyroid hormone receptor β, and glucocorticoid receptor, as well as other transcription factors, such as FoxO1 (2Tcherepanova I. Puigserver P. Norris J.D. Spiegelman B.M. McDonnell D.P. J. Biol. Chem. 2000; 275: 16302-16308Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar, 3Knutti D. Kaul A. Kralli A. Mol. Cell. Biol. 2000; 20: 2411-2422Crossref PubMed Scopus (240) Google Scholar, 4Puigserver P. Rhee J. Donovan J. Walkey C.J. Yoon J.C. Oriente F. Kitamura Y. Altomonte J. Dong H. Accili D. Spiegelman B.M. Nature. 2003; 423: 550-555Crossref PubMed Scopus (1154) Google Scholar, 5Puigserver P. Spiegelman B.M. Endocr. Rev. 2003; 24: 78-90Crossref PubMed Scopus (1590) Google Scholar, 6Lin J. Handschin C. Spiegelman B.M. Cell. Metab. 2005; 1: 361-370Abstract Full Text Full Text PDF PubMed Scopus (1634) Google Scholar, 7Rodgers J.T. Lerin C. Gerhart-Hines Z. Puigserver P. FEBS Lett. 2008; 582: 46-53Crossref PubMed Scopus (490) Google Scholar). PGC-1α is regulated by several signaling pathways and post-translational modifications (7Rodgers J.T. Lerin C. Gerhart-Hines Z. Puigserver P. FEBS Lett. 2008; 582: 46-53Crossref PubMed Scopus (490) Google Scholar). Protein arginine methyltransferase PRMT1 potentiates the coactivator function of PGC-1α by methylating three C-terminal amino acid residues Arg665, Arg667, and Arg669 within its RNA-binding domain (8Teyssier C. Ma H. Emter R. Kralli A. Stallcup M.R. Genes Dev. 2005; 19: 1466-1473Crossref PubMed Scopus (190) Google Scholar). Distinct protein kinases exert complex regulation via targeting several sites in PGC-1α. Phosphorylation of Thr177 and Ser538 by AMP-activated protein kinase (AMPK) augments the coactivation function of PGC-1α (9Jager S. Handschin C. St-Pierre J. Spiegelman B.M. Proc. Natl. Acad. Sci. U.S.A. 2007; 104: 12017-12022Crossref PubMed Scopus (1749) Google Scholar), whereas protein kinase kinase of can PGC-1α Nature. 2007; PubMed Scopus Google Scholar). Phosphorylation of PGC-1α amino acid residues and by in to activation of the PGC-1α, in via the of protein from PGC-1α P. Rhee J. J. Wu Z. Yoon J.C. S. Spiegelman B.M. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, M. Rhee J. St-Pierre J. Handschin C. Puigserver P. J. S. H. P. Spiegelman B.M. Genes Dev. PubMed Scopus Google Scholar). Interestingly, the sites with by kinase can target the protein for and S. Kralli A. Genes Dev. 2008; PubMed Scopus Google Scholar). PGC-1α several lysine the protein J.T. Lerin C. Spiegelman B.M. Puigserver P. Nature. 2005; PubMed Scopus Google Scholar). of amino acid PGC-1α, its coactivator activity Puigserver Full Text Full Text PDF PubMed Scopus Google Scholar). The be to of PGC-1α to it with transcriptional such as RIP140. activity of can PGC-1α in an and to J.T. Lerin C. Spiegelman B.M. Puigserver P. Nature. 2005; PubMed Scopus Google Scholar, S. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). peroxisome proliferator-activated receptor γ coactivator peroxisome proliferator-activated receptor γ small ubiquitin-like modifier protein kinase protein inhibitor of activated signal transducers and activators of transcription protein AMP-activated protein kinase carrier protein isopeptide inhibitor estrogen receptor-related receptor. peroxisome proliferator-activated receptor γ coactivator peroxisome proliferator-activated receptor γ small ubiquitin-like modifier protein kinase protein inhibitor of activated signal transducers and activators of transcription protein AMP-activated protein kinase carrier protein isopeptide inhibitor estrogen receptor-related receptor. to and lysine residues can be covalently modified by and ubiquitin-like three small ubiquitin-like modifier (SUMO) and that of amino and can isopeptide with of is with whereas and D. H. 2007; PubMed Scopus Google Scholar, F. Cell. 1: PubMed Scopus Google Scholar). Although and a amino acid and to the of lysine is found within a consensus is a and is M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). is not to whereas and can The SUMO is to that of but and for first activated in an by the and and by and protein able to SUMOylation in a that the of F. M. A. Sci. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). SUMOylation is not a but is by and The can be by a of Biol. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). SUMOylation as a in in transcription and signal the can in a the subcellular and localization of the protein, its to interact with other its activity in transcription in F. Cell. 1: PubMed Scopus Google and P. Biol. 2007; 19: PubMed Scopus Google Scholar). the same lysine residue can be by or the can a protein from of SUMO can interact with in and J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, A. Biol. 2008; PubMed Scopus Google Scholar). to targeting a of transcription factors, SUMOylation to transcriptional such as and and such as and D. D. A. Mol. Cell. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, H. Y. Y. R. Y. J. D. Wu D. S. Y. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, A. M. A. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J. M. M. F. Mol. Biol. Cell. PubMed Scopus Google Scholar, J. Biol. Chem. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). Here, we show that reversible SUMOylation can the transcriptional activity of PGC-1α an apparent effect on its we have of the transcriptional coactivator PGC-1α and show that the lysine residue 183 that is located in the transcription activation domain of PGC-1α is to reversible The lysine to the SUMO consensus and the site is from to The coactivator PGC-1α also that the but the site was not to by Interestingly, is also the residues in PGC-1α that by PGC-1α an site to to a to the effect of J.T. Lerin C. Spiegelman B.M. Puigserver P. Nature. 2005; PubMed Scopus Google Scholar). have not the role of for the function of the coactivator. Interestingly, mutation of to and a enhancing effect on the transcriptional activity of PGC-1α. Mutation of the residue the in the SUMOylation consensus SUMOylation but is to and also and to the role of SUMOylation from the other lysine modifications in the PGC-1α function. Interestingly, the E185A was also the coactivator. the context of isolated N-terminal activation the E185A transcriptional activity the with of the activation of the SUMOylation consensus of PGC-1α its as a coactivator for and transcription. the coactivator activity in the context of nuclear receptors, results that and SUMOylation have in the regulation of PGC-1α function in the nuclear receptor we the that the of the SUMOylation consensus the of It is also that is by other lysine such as and and be a or a lysine Although was the major sites and the SUMOylation site of PGC-1α, signaling was able to the SUMOylation of PGC-1α. via of the SUMOylation N-terminal domain of PGC-1α motifs M. S. C. J. S. M. S. F. H. J. Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar), the C-terminal of with of the S. Kralli A. Genes Dev. 2008; PubMed Scopus Google Scholar). The SUMOylation site of PGC-1α the but our not in the stability or of the PGC-1α with the of with inhibitor results in of PGC-1α protein and of of PGC-1α M. S. C. J. S. M. S. F. H. J. Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). a in but the effect of the inhibitor on the not the and the PGC-1α Our that PGC-1α the of in small in the is in with the Puigserver Full Text Full Text PDF PubMed Scopus Google Scholar, M. S. C. J. S. M. S. F. H. J. Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). of the SUMOylation site of PGC-1α not the nuclear of in the same lysine residue can be by or SUMOylation transcription and Cell. 2005; PubMed Scopus Google Scholar, Mol. Cell. Biol. 2005; PubMed Scopus Google Scholar, S. J. S. C. A. D. Mol. Cell. Biol. 2007; PubMed Scopus Google Scholar). the of in is an the of modifications in that the activation of that results in SUMOylation of the same lysine residue S. J. S. C. A. D. Mol. Cell. Biol. 2007; PubMed Scopus Google Scholar). and SUMOylation was not with PGC-1α, of the activity by not show apparent effect on the SUMOylation of including and to interact with the N-terminal activation domain of PGC-1α (7Rodgers J.T. Lerin C. Gerhart-Hines Z. Puigserver P. FEBS Lett. 2008; 582: 46-53Crossref PubMed Scopus (490) Google Scholar, P. Wu Z. M. J. Spiegelman B.M. PubMed Scopus Google Scholar). SUMO is a the effect of the SUMOylation be to the that the from with the activation we not the PGC-1α and its SUMOylation with to to and in our transcription the other SUMOylation of PGC-1α with such as to PGC-1α and with it in the same Puigserver Full Text Full Text PDF PubMed Scopus Google Scholar, M. Kralli A. R. M. Mol. Cell. Biol. 2008; PubMed Google Scholar). of the corepressor we found that of the SUMOylation consensus E185A the transcription activation function of PGC-1α to the by RIP140. our that the can a role in and of to the Interestingly, is also covalently modified by J. Biol. Chem. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar), but its SUMOylation does not to a role in the of and with Puigserver Full Text Full Text PDF PubMed Scopus Google Scholar). to our and but not the for the SUMOylation of PGC-1α. be in the regulation of PGC-1α protein and SUMOylation of such as transcription β, is a corepressor regulated by SUMOylation and is also found in complex with PGC-1α Puigserver Full Text Full Text PDF PubMed Scopus Google Scholar, D. P. P. M. J. Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google our that the N-terminal domain of PGC-1α is to reversible SUMO that its to function as a transcriptional coactivator a novel to the regulation of the PGC-1α The SUMOylation as a to PGC-1α activity cellular activity the we have of the transcriptional coactivator PGC-1α and show that the lysine residue 183 that is located in the transcription activation domain of PGC-1α is to reversible The lysine to the SUMO consensus and the site is from to The coactivator PGC-1α also that the but the site was not to by Interestingly, is also the residues in PGC-1α that by PGC-1α an site to to a to the effect of J.T. Lerin C. Spiegelman B.M. Puigserver P. Nature. 2005; PubMed Scopus Google Scholar). have not the role of for the function of the coactivator. Interestingly, mutation of to and a enhancing effect on the transcriptional activity of PGC-1α. Mutation of the residue the in the SUMOylation consensus SUMOylation but is to and also and to the role of SUMOylation from the other lysine modifications in the PGC-1α function. Interestingly, the E185A was also the coactivator. the context of isolated N-terminal activation the E185A transcriptional activity the with of the activation of the SUMOylation consensus of PGC-1α its as a coactivator for and transcription. the coactivator activity in the context of nuclear receptors, results that and SUMOylation have in the regulation of PGC-1α function in the nuclear receptor we the that the of the SUMOylation consensus the of It is also that is by other lysine such as and and be a or a lysine Although was the major sites and the SUMOylation site of PGC-1α, signaling was able to the SUMOylation of PGC-1α. via of the SUMOylation The N-terminal domain of PGC-1α motifs M. S. C. J. S. M. S. F. H. J. Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar), the C-terminal of with of the S. Kralli A. Genes Dev. 2008; PubMed Scopus Google Scholar). The SUMOylation site of PGC-1α the but our not in the stability or of the PGC-1α with the of with inhibitor results in of PGC-1α protein and of of PGC-1α M. S. C. J. S. M. S. F. H. J. Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). a in but the effect of the inhibitor on the not the and the PGC-1α Our that PGC-1α the of in small in the is in with the Puigserver Full Text Full Text PDF PubMed Scopus Google Scholar, M. S. C. J. S. M. S. F. H. J. Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). of the SUMOylation site of PGC-1α not the nuclear of in the same lysine residue can be by or SUMOylation transcription and Cell. 2005; PubMed Scopus Google Scholar, Mol. Cell. Biol. 2005; PubMed Scopus Google Scholar, S. J. S. C. A. D. Mol. Cell. Biol. 2007; PubMed Scopus Google Scholar). the of in is an the of modifications in that the activation of that results in SUMOylation of the same lysine residue S. J. S. C. A. D. Mol. Cell. Biol. 2007; PubMed Scopus Google Scholar). and SUMOylation was not with PGC-1α, of the activity by not show apparent effect on the SUMOylation of PGC-1α. including and to interact with the N-terminal activation domain of PGC-1α (7Rodgers J.T. Lerin C. Gerhart-Hines Z. Puigserver P. FEBS Lett. 2008; 582: 46-53Crossref PubMed Scopus (490) Google Scholar, P. Wu Z. M. J. Spiegelman B.M. PubMed Scopus Google Scholar). SUMO is a the effect of the SUMOylation be to the that the from with the activation we not the PGC-1α and its SUMOylation with to to and in our transcription the other SUMOylation of PGC-1α with such as to PGC-1α and with it in the same Puigserver Full Text Full Text PDF PubMed Scopus Google Scholar, M. Kralli A. R. M. Mol. Cell. Biol. 2008; PubMed Google Scholar). of the corepressor we found that of the SUMOylation consensus E185A the transcription activation function of PGC-1α to the by RIP140. our that the can a role in and of to the Interestingly, is also covalently modified by J. Biol. Chem. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar), but its SUMOylation does not to a role in the of and with Puigserver Full Text Full Text PDF PubMed Scopus Google Scholar). to our and but not the for the SUMOylation of PGC-1α. be in the regulation of PGC-1α protein and SUMOylation of such as transcription β, is a corepressor regulated by SUMOylation and is also found in complex with PGC-1α Puigserver Full Text Full Text PDF PubMed Scopus Google Scholar, D. P. P. M. J. Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). our that the N-terminal domain of PGC-1α is to reversible SUMO that its to function as a transcriptional coactivator a novel to the regulation of the PGC-1α The SUMOylation as a to PGC-1α activity cellular activity the for and for the