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Cell Rep. 2017 Jun 13;19(11):2331-2344. doi: 10.1016/j.celrep.2017.05.065.

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

Author information

1
Department of Systems Biology for Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
2
Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
3
Department of Immunity, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
4
Department of Clinical Laboratory, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China.
5
Department of Systems Biology for Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China. Electronic address: pyyang@fudan.edu.cn.
6
Department of Systems Biology for Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China. Electronic address: hongxiuyu@fudan.edu.cn.

Abstract

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.

KEYWORDS:

IL-1β; PKM2; SIRT5; colitis; macrophages; succinylation

PMID:
28614718
DOI:
10.1016/j.celrep.2017.05.065
[Indexed for MEDLINE]
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