title: SIRT3 functions in the nucleus in the control of stress-related gene expression.
abstract: SIRT3 is a member of the Sir2 family of NAD(+)-dependent protein deacetylases that promotes longevity in many organisms. The processed short form of SIRT3 is a well-established mitochondrial protein whose deacetylase activity regulates various metabolic processes. However, the presence of full-length (FL) SIRT3 in the nucleus and its functional importance remain controversial. Our previous studies demonstrated that nuclear FL SIRT3 functions as a histone deacetylase and is transcriptionally repressive when artificially recruited to a reporter gene. Here, we report that nuclear FL SIRT3 is subjected to rapid degradation under conditions of cellular stress, including oxidative stress and UV irradiation, whereas the mitochondrial processed form is unaffected. FL SIRT3 degradation is mediated by the ubiquitin-proteasome pathway, at least partially through the ubiquitin protein ligase (E3) activity of SKP2. Finally, we show by chromatin immunoprecipitation that some target genes of nuclear SIRT3 are derepressed upon degradation of SIRT3 caused by stress stimuli. Thus, SIRT3 exhibits a previously unappreciated role in the nucleus, modulating the expression of some stress-related and nuclear-encoded mitochondrial genes.
authors.affiliation: Howard Hughes Medical Institute, Department of Biochemistry, New York University School of Medicine, New York, New York, USA.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Iwahara
authors.forename: Roberto
authors.initials: R
authors.lastname: Bonasio
authors.forename: Varun
authors.initials: V
authors.lastname: Narendra
authors.forename: Danny
authors.initials: D
authors.lastname: Reinberg
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D018384:Oxidative Stress; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D017384:Sequence Deletion; D056566:Sirtuin 3 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D014466:Ultraviolet Rays
chemical_list: D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D044786:S-Phase Kinase-Associated Proteins; D044767:Ubiquitin-Protein Ligases; C466093:SIRT3 protein, human; D056566:Sirtuin 3