SIRT1 sumoylation regulates its deacetylase activity and cellular response to genotoxic stress.
SIRT1 is the closest mammalian homologue of yeast SIR2, an important ageing regulator that prolongs lifespan in response to caloric restriction. Despite its importance, the mechanisms that regulate SIRT1 activity are unclear. Our study identifies a novel post-translational modification of SIRT1, namely sumoylation at Lys 734. In vitro sumoylation of SIRT1 increased its deacetylase activity. Conversely, mutation of SIRT1 at Lys 734 or desumoylation by SENP1, a nuclear desumoylase, reduced its deacetylase activity. Stress-inducing agents promoted the association of SIRT1 with SENP1 and cells depleted of SENP1 (but not of SENP1 and SIRT1) were more resistant to stress-induced apoptosis than control cells. We suggest that stress-inducing agents counteract the anti-apoptotic activity of SIRT1 by recruiting SENP1 to SIRT1, which results in the desumoylation and inactivation of SIRT1 and the consequent acetylation and activation of apoptotic proteins.
Yang
Yonghua
Y
Departments of Pathology and Cell Biology, University of South Florida College of Medicine, 12901 Bruce B. Downs Blvd., Tampa, Florida 33612-4799, USA.
Fu
Wei
W
Chen
Jiandong
J
Olashaw
Nancy
N
Zhang
Xiaohong
X
Nicosia
Santo V
SV
Bhalla
Kapil
K
Bai
Wenlong
W
D000107:Acetylation; D000115:Acetylesterase / Q000187:drug effects*; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D003546:Cysteine Endopeptidases; D004249:DNA Damage; D010450:Endopeptidases / Q000378:metabolism; D006801:Humans; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000378:metabolism; D056564:Sirtuin 1; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D011506:Proteins; D025841:Small Ubiquitin-Related Modifier Proteins; D016159:Tumor Suppressor Protein p53; D000115:Acetylesterase; D010450:Endopeptidases; C404512:SENP1 protein, human; D003546:Cysteine Endopeptidases; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins