| First Author | Wang F | Year | 2017 |
| Journal | Cell Rep | Volume | 19 |
| Issue | 11 | Pages | 2331-2344 |
| PubMed ID | 28614718 | Mgi Jnum | J:254358 |
| Mgi Id | MGI:6103125 | Doi | 10.1016/j.celrep.2017.05.065 |
| Citation | Wang F, et al. (2017) SIRT5 Desuccinylates and Activates Pyruvate Kinase M2 to Block Macrophage IL-1beta Production and to Prevent DSS-Induced Colitis in Mice. Cell Rep 19(11):2331-2344 |
| abstractText | 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-HIF1alpha is formed at the promoter of IL-1beta gene in LPS-stimulated macrophages. Activation of PKM2 using TEPP-46 attenuates Sirt5-deficiency-mediated IL-1beta 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-1beta 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. |
