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 and Toren Finkel ()
Additional contact information
Nisha Narayan: Center for Molecular Medicine, National Heart, Lung and Blood Institute
In Hye Lee: Center for Molecular Medicine, National Heart, Lung and Blood Institute
Ronen Borenstein: Center for Molecular Medicine, National Heart, Lung and Blood Institute
Junhui Sun: Systems Biology Center, National Heart, Lung and Blood Institute
Renee Wong: Systems Biology Center, National Heart, Lung and Blood Institute
Guang Tong: Systems Biology Center, National Heart, Lung and Blood Institute
Maria M. Fergusson: Center for Molecular Medicine, National Heart, Lung and Blood Institute
Jie Liu: Center for Molecular Medicine, National Heart, Lung and Blood Institute
Ilsa I. Rovira: Center for Molecular Medicine, National Heart, Lung and Blood Institute
Hwei-Ling Cheng: Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Harvard Medical School
Guanghui Wang: Proteomics Core, National Heart, Lung and Blood Institute
Marjan Gucek: Proteomics Core, National Heart, Lung and Blood Institute
David Lombard: University of Michigan
Fredrick W. Alt: Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Harvard Medical School
Michael N. Sack: Center for Molecular Medicine, National Heart, Lung and Blood Institute
Elizabeth Murphy: Systems Biology Center, National Heart, Lung and Blood Institute
Liu Cao: Key Laboratory of Medical Cell Biology, China Medical University
Toren Finkel: Center for Molecular Medicine, National Heart, Lung and Blood Institute

Nature, 2012, vol. 492, issue 7428, 199-204

Abstract: 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.

Date: 2012
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DOI: 10.1038/nature11700

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