title: A high-confidence interaction map identifies SIRT1 as a mediator of acetylation of USP22 and the SAGA coactivator complex.
abstract: Although many functions and targets have been attributed to the histone and protein deacetylase SIRT1, a comprehensive analysis of SIRT1 binding proteins yielding a high-confidence interaction map has not been established. Using a comparative statistical analysis of binding partners, we have assembled a high-confidence SIRT1 interactome. Employing this method, we identified the deubiquitinating enzyme ubiquitin-specific protease 22 (USP22), a component of the deubiquitinating module (DUBm) of the SAGA transcriptional coactivating complex, as a SIRT1-interacting partner. We found that this interaction is highly specific, requires the ZnF-UBP domain of USP22, and is disrupted by the inactivating H363Y mutation within SIRT1. Moreover, we show that USP22 is acetylated on multiple lysine residues and that alteration of a single lysine (K129) within the ZnF-UBP domain is sufficient to alter interaction of the DUBm with the core SAGA complex. Furthermore, USP22-mediated recruitment of SIRT1 activity promotes the deacetylation of individual SAGA complex components. Our results indicate an important role of SIRT1-mediated deacetylation in regulating the formation of DUBm subcomplexes within the larger SAGA complex.
authors: Department of Genetics and The Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, Boston, Massachusetts, USA.
authors: Sean M
authors: SM
authors: Armour
authors: Eric J
authors: EJ
authors: Bennett
authors: Craig R
authors: CR
authors: Braun
authors: Xiao-Yong
authors: XY
authors: Zhang
authors: Steven B
authors: SB
authors: McMahon
authors: Steven P
authors: SP
authors: Gygi
authors: J Wade
authors: JW
authors: Harper
authors: David A
authors: DA
authors: Sinclair
mesh_terms: D000107:Acetylation; D002460:Cell Line; D057809:HEK293 Cells; D006801:Humans; D009154:Mutation; D011485:Protein Binding; D060066:Protein Interaction Maps; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D034741:RNA, Small Interfering; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D013869:Thiolester Hydrolases / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D043222:Ubiquitin Thiolesterase; D054875:Ubiquitination
chemical_list: D034741:RNA, Small Interfering; D015534:Trans-Activators; D013869:Thiolester Hydrolases; D043222:Ubiquitin Thiolesterase; C527170:Usp22 protein, human; C447939:SIRT1 protein, human; D056564:Sirtuin 1
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