SIRT5 Desuccinylates and Activates Pyruvate Kinase M2 to Block Macrophage IL-1β Production and to Prevent DSS-Induced Colitis in Mice

Publication date: 13 June 2017
Source:Cell Reports, Volume 19, Issue 11
Author(s): Fang Wang, Ke Wang, Wei Xu, Shimin Zhao, Dan Ye, Yi Wang, Ying Xu, Lisha Zhou, Yiwei Chu, Cuiping Zhang, Xue Qin, Pengyuan Yang, Hongxiu Yu
LPS-activated macrophages undergo a metabolic shift from dependence on mitochondria-produced ATP to reliance on aerobic glycolysis, where PKM2 is a critical determinant. Here, we show that PKM2 is a physiological substrate of SIRT5 and that SIRT5-regulated hypersuccinylation inhibits the pyruvate kinase activity of PKM2 by promoting its tetramer-to-dimer transition. Moreover, a succinylation-mimetic PKM2 K311E mutation promotes nuclear accumulation and increases protein kinase activity. Furthermore, we show that SIRT5-dependent succinylation promotes PKM2 entry into nucleus, where a complex of PKM2-HIF1α is formed at the promoter of IL-1β gene in LPS-stimulated macrophages. Activation of PKM2 using TEPP-46 attenuates Sirt5-deficiency-mediated IL-1β upregulation in LPS-stimulated macrophages. Finally, we find that Sirt5-deficient mice are more susceptible to DSS-induced colitis, which is associated with Sirt5 deficiency prompted PKM2 hypersuccinylation and boosted IL-1β production. In conclusion, our findings reveal a mechanism by which SIRT5 suppresses the pro-inflammatory response in macrophages at least in part by regulating PKM2 succinylation, activity, and function.

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Teaser

Activated immune cells reprogram their metabolism in infection or injury response. Wang et al. reveal that SIRT5 desuccinylates and activates PKM2 to block macrophage IL-1β production and to prevent DSS-induced colitis in mice, highlighting the role of SIRT5 and PKM2 in the process of macrophage metabolic reprogramming, sirtuin biology, and inflammation.


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