Tumor necrosis factor-α (TNF-α) elicits programmed necrosis, or necroptosis, by stimulating an interaction between the RIP1 and RIP3 kinases. However, the mechanisms regulating RIP1–RIP3 complex formation and the induction of necroposis remain incompletely defined. Finkel and colleagues report that the deacetylase SIRT2 has an important role in these processes (Nature http://doi.org/jx3; 2012).

The authors found that SIRT2 interacts directly with RIP3 in vitro and in vivo. Intriguingly, SIRT2 deletion or depletion blocked TNF-α-stimulated RIP1–RIP3 complex formation and necroptosis induction. Similar results were observed on treatment with the SIRT2 deacetylase inhibitor AGK2, suggesting that the catalytic activity of SIRT2 is critical for these effects.

Indeed, RIP1 is acetylated under basal conditions, but acetylation decreased following TNF-α treatment. RIP1 was shown to be a direct target of SIRT2, and knocking down SIRT2 or expressing a catalytically inactive SIRT2 mutant attenuated RIP1 deacetylation in vivo. Moreover, an acetylation-deficient RIP1 mutant formed a constitutive complex with RIP3 and efficiently induced necroptosis following TNF-α treatment.

Finkel and colleagues also showed that Sirt2 loss or inhibition promoted recovery in a mouse model of ischemia-reperfusion injury, where blocking necrosis is known to have a protective effect. Their findings provide fresh insight into the mechanisms regulating necroptosis, and suggest that SIRT2 inhibition might be a clinically relevant strategy to treat diseases involving necrosis.