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The NAD-dependent deacetylase SIRT2 is required for programmed necrosis

A Retraction to this article was published on 26 February 2014

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.

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Figure 1: SIRT2 interacts with RIP3 and regulates RIP1–RIP3 complex formation.
Figure 2: Inhibition of SIRT2 prevents cellular necrosis.
Figure 3: RIP1 is a target of SIRT2-dependent deacetylation.
Figure 4: Acetylation status of RIP1 lysine 530 regulates necrosis.
Figure 5: Inhibition of SIRT2 protects against ischaemia-reperfusion injury.

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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.

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N.N., I.H.L, R.B., J.S., R.W., G.T., M.M.F., J.L., G.W. and L.C. carried out experimental work and analysed data, H.-L.C., F.W.A., D.L. and M.N.S. provided critical materials and data interpretation, M.G. and E.M. supervised the research, I.I.R. analysed the data, T.F. supervised the research and wrote the manuscript.

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Correspondence to Toren Finkel.

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Narayan, N., Lee, I., Borenstein, R. et al. The NAD-dependent deacetylase SIRT2 is required for programmed necrosis. Nature 492, 199–204 (2012). https://doi.org/10.1038/nature11700

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