title: C. elegans SIRT6/7 homolog SIR-2.4 promotes DAF-16 relocalization and function during stress.
abstract: FoxO transcription factors and sirtuin family deacetylases regulate diverse biological processes, including stress responses and longevity. Here we show that the Caenorhabditis elegans sirtuin SIR-2.4--homolog of mammalian SIRT6 and SIRT7 proteins--promotes DAF-16-dependent transcription and stress-induced DAF-16 nuclear localization. SIR-2.4 is required for resistance to multiple stressors: heat shock, oxidative insult, and proteotoxicity. By contrast, SIR-2.4 is largely dispensable for DAF-16 nuclear localization and function in response to reduced insulin/IGF-1-like signaling. Although acetylation is known to regulate localization and activity of mammalian FoxO proteins, this modification has not been previously described on DAF-16. We find that DAF-16 is hyperacetylated in sir-2.4 mutants. Conversely, DAF-16 is acetylated by the acetyltransferase CBP-1, and DAF-16 is hypoacetylated and constitutively nuclear in response to cbp-1 inhibition. Surprisingly, a SIR-2.4 catalytic mutant efficiently rescues the DAF-16 localization defect in sir-2.4 null animals. Acetylation of DAF-16 by CBP-1 in vitro is inhibited by either wild-type or mutant SIR-2.4, suggesting that SIR-2.4 regulates DAF-16 acetylation indirectly, by preventing CBP-1-mediated acetylation under stress conditions. Taken together, our results identify SIR-2.4 as a critical regulator of DAF-16 specifically in the context of stress responses. Furthermore, they reveal a novel role for acetylation, modulated by the antagonistic activities of CBP-1 and SIR-2.4, in modulating DAF-16 localization and function.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Wei-Chung
authors.initials: WC
authors.lastname: Chiang
authors.forename: Daniel X
authors.initials: DX
authors.lastname: Tishkoff
authors.forename: Bo
authors.initials: B
authors.lastname: Yang
authors.forename: Joshua
authors.initials: J
authors.lastname: Wilson-Grady
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Yu
authors.forename: Travis
authors.initials: T
authors.lastname: Mazer
authors.forename: Mark
authors.initials: M
authors.lastname: Eckersdorff
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.forename: David B
authors.initials: DB
authors.lastname: Lombard
authors.forename: Ao-Lin
authors.initials: AL
authors.lastname: Hsu
mesh_terms: D000107:Acetylation; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D051858:Forkhead Transcription Factors; D018869:Heat-Shock Response / Q000235:genetics / Q000502:physiology; D051548:Histone Acetyltransferases / Q000378:metabolism; D008136:Longevity / Q000235:genetics / Q000502:physiology; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology
chemical_list: D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; D014157:Transcription Factors; C108831:daf-16 protein, C elegans; C111709:CBP-1 protein, C elegans; D051548:Histone Acetyltransferases; D037761:Sirtuins