The NAD-dependent deacetylase SIRT2 is required for programmed necrosis

Nisha Narayan, In Hye Lee, Ronen Borenstein, Junhui Sun, Renee Wong, Guang Tong, Maria M. Fergusson, Jie Liu, Ilsa I. Rovira, Hwei Ling Cheng, Guanghui Wang, Marjan Gucek, David Lombard, Fredrick W. Alt, Michael N. Sack, Elizabeth Murphy, Liu Cao, Toren Finkel

Research output: Contribution to journalArticlepeer-review

125 Scopus citations

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.

Original languageEnglish
Pages (from-to)199-204
Number of pages6
JournalNature
Volume492
Issue number7428
DOIs
StatePublished - 13 Dec 2012

Bibliographical note

Funding Information:
Acknowledgements We are grateful to M. Lenardo for providing the RIP1-deficient Jurkat cell line, X. Wang for the Flag-tagged RIP3 plasmid and Y. Zhao for helpful discussions. This work was supported by NIH Intramural funds. F.W.A. is an Investigator of the Howard Hughes Medical Institute.

Fingerprint

Dive into the research topics of 'The NAD-dependent deacetylase SIRT2 is required for programmed necrosis'. Together they form a unique fingerprint.

Cite this