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Is SIRT2 required for necroptosis?



Arising from N. Narayan et al. Nature 492, 199–204 (2012)10.1038/nature11700

Sirtuins can promote deacetylation of a wide range of substrates in diverse cellular compartments to regulate many cellular processes1,2; recently, Narayan et al.3 reported that SIRT2 was required for necroptosis on the basis of their findings that SIRT2 inhibition, knockdown or knockout prevented necroptosis. We sought to confirm and explore the role of SIRT2 in necroptosis and tested four different sources of the SIRT2 inhibitor AGK2, three independent short interfering RNAs (siRNAs) against Sirt2, and cells from two independently generated Sirt2−/− mouse strains; however, we were unable to show that inhibiting or depleting SIRT2 protected cells from necroptosis. Furthermore, Sirt2−/− mice succumbed to tumour-necrosis factor (TNF)-induced systemic inflammatory response syndrome (SIRS) more rapidly than wild-type mice, whereas Ripk3−/− mice were resistant. Our results therefore question the importance of SIRT2 in the necroptosis cell death pathway.

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Figure 1: Neither chemical inhibition nor genetic depletion of SIRT2 inhibits TNF-induced necroptosis.
Figure 2: Appendix Figure 1 Neither chemical inhibition nor genetic depletion of SIRT2 inhibits TNF-induced necroptosis.

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K.N., J.M.H., Z.S., D.R., S.A.-D., S.P., S.S., D.L.D. and C.H. designed and performed experiments and analysed data; J.A., P.V., D.R.G., A.A., V.M.D., W.J.K., A.S., A.D. and J.S. planned the project and performed data analysis; K.N., J.M.H., J.A., P.V., D.R.G., A.A., V.M.D., W.J.K., A.S., A.D. and J.S. wrote paper.

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Correspondence to John Silke.

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Newton, K., Hildebrand, J., Shen, Z. et al. Is SIRT2 required for necroptosis?. Nature 506, E4–E6 (2014).

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