SIRT5 desuccinylates and activates pyruvate kinase M2 to block macrophage IL-1β production and to prevent DSS-induced colitis in mice Wang, F et al. Cell Reports 2017; 19: 2331-44 Speaker: Yi-Shiang Wang (王奕翔) Time: 15:10-1600, Nov. 22, 2017 Commentator: Dr. Chrong-Reen Wong (王崇任 醫師) Place: Room 601 Abstract: Similar to Warburg effect occurring in tumor cells, LPS-activated macrophages encounter metabolic shifts, including higher reliance on aerobic glycolysis, in which pyruvate kinase M2 (PKM2) plays a critical role [1]. Sirtuin 5 (SIRT5), which belongs to HDACs (histone deacetylase) family, can desuccinylate lysine residues on various proteins and impact diverse metabolic pathways. Previous studies have identified PKM2 as a potential succinylation substrate of SIRT5. PKM2 exists in homotetrameric and homodimeric forms, in which dimeric form in mostly inactive, but the tetramer is highly active at physiological phosphoenolpyruvate (PEP) concentrations. In this study, the authors used SIRT5 knockdown human cells and Sirt5 knockout mice to investigate whether SIRT5 regulates PKM2 activity/function through lysine succinylation, thus modulating IL-1β production in LPS-activated macrophages and impacting inflammation. They found that SIRT5 directly interacts with and desuccinylates PKM2, thereby inhibiting the tetramer-to-dimer transition of PKM2 to maintain its pyruvate kinase activity. In contrast, succinylation of PKM2 at lysine 311 promotes its tetramer-to-dimer transition. Moreover, the dimeric PKM2 translocates into the nucleus and forms a transcriptional complex with HIF-1α that directly binds to the IL-1β promoter and activates its transcription in LPS-activated macrophages. The authors further exploited a mouse model of dextran sulfate sodium (DSS)-induced colitis that resembles human inflammatory bowel disease (IBD) to elucidate the role of SIRT5 in inflammatory conditions. Compared to wild-type mice, Sirt5 knockout mice are highly susceptible to inflammatory colitis. Furthermore, both PKM2 activation and IL-1β neutralization confer protection against DSS-induced colitis in Sirt5 knockout mice. In conclusion, these results indicate that SIRT5 desuccinylates and activates PKM2 to inhibit IL-1β production and to prevent inflammatory colitis in mice. Therefore, SIRT5 and PKM2 play important roles in the process of inflammation and macrophage metabolic reprogramming. References: 1. Palsson-McDermott, EM et al. Pyruvate kinase M2 regulateds Hif-1α activity and IL-1β induction and is a critical determinant of the warbug effect in LPS-activated macrophages. Cell Metab. 2015; 21: 65-80 2. Witney, TH et al. PET imaging of tumor glycolysis downstream of hexokinase through noninvasive measurement of pyruvate kinase M2. Sci. Transl. Med. 2015; 7(310): 310ra169.