title: The NAD-dependent deacetylase SIRT2 is required for programmed necrosis.
abstract: Although initially viewed as unregulated, increasing evidence suggests that cellular necrosis often proceeds through a specific molecular program. In particular, death ligands such as tumour necrosis factor (TNF)-α activate necrosis by stimulating the formation of a complex containing receptor-interacting protein 1 (RIP1) and receptor-interacting protein 3 (RIP3). Relatively little is known regarding how this complex formation is regulated. Here, we show that the NAD-dependent deacetylase SIRT2 binds constitutively to RIP3 and that deletion or knockdown of SIRT2 prevents formation of the RIP1-RIP3 complex in mice. Furthermore, genetic or pharmacological inhibition of SIRT2 blocks cellular necrosis induced by TNF-α. We further demonstrate that RIP1 is a critical target of SIRT2-dependent deacetylation. Using gain- and loss-of-function mutants, we demonstrate that acetylation of RIP1 lysine 530 modulates RIP1-RIP3 complex formation and TNF-α-stimulated necrosis. In the setting of ischaemia-reperfusion injury, RIP1 is deacetylated in a SIRT2-dependent fashion. Furthermore, the hearts of Sirt2(-/-) mice, or wild-type mice treated with a specific pharmacological inhibitor of SIRT2, show marked protection from ischaemic injury. Taken together, these results implicate SIRT2 as an important regulator of programmed necrosis and indicate that inhibitors of this deacetylase may constitute a novel approach to protect against necrotic injuries, including ischaemic stroke and myocardial infarction.
authors.affiliation: Center for Molecular Medicine, National Heart, Lung and Blood Institute, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Nisha
authors.initials: N
authors.lastname: Narayan
authors.forename: In Hye
authors.initials: IH
authors.lastname: Lee
authors.forename: Ronen
authors.initials: R
authors.lastname: Borenstein
authors.forename: Junhui
authors.initials: J
authors.lastname: Sun
authors.forename: Renee
authors.initials: R
authors.lastname: Wong
authors.forename: Guang
authors.initials: G
authors.lastname: Tong
authors.forename: Maria M
authors.initials: MM
authors.lastname: Fergusson
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Ilsa I
authors.initials: II
authors.lastname: Rovira
authors.forename: Hwei-Ling
authors.initials: HL
authors.lastname: Cheng
authors.forename: Guanghui
authors.initials: G
authors.lastname: Wang
authors.forename: Marjan
authors.initials: M
authors.lastname: Gucek
authors.forename: David
authors.initials: D
authors.lastname: Lombard
authors.forename: Fredrick W
authors.initials: FW
authors.lastname: Alt
authors.forename: Michael N
authors.initials: MN
authors.lastname: Sack
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Murphy
authors.forename: Liu
authors.initials: L
authors.lastname: Cao
authors.forename: Toren
authors.initials: T
authors.lastname: Finkel
mesh_terms: D000107:Acetylation; D000818:Animals; D002460:Cell Line; D005260:Female; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D008297:Male; D051379:Mice; D009336:Necrosis / Q000201:enzymology*; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism; D011485:Protein Binding; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D056565:Sirtuin 2 / Q000235:genetics* / Q000378:metabolism*
chemical_list: D028861:Nuclear Pore Complex Proteins; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D056565:Sirtuin 2