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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Colitis / immunology*
  • Colitis / metabolism
  • Humans
  • Interleukin-1beta / biosynthesis*
  • Interleukin-1beta / immunology
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Phosphorylation
  • Pyruvate Kinase / immunology*
  • Pyruvate Kinase / metabolism
  • Signal Transduction
  • Sirtuins / immunology*
  • Sirtuins / metabolism
  • Transfection


  • Interleukin-1beta
  • Pyruvate Kinase
  • SIRT5 protein, human
  • Sirtuins