Abstract
Several enzymes involved in central carbon metabolism such as isocitrate lyase and phosphoenolpyruvate carboxykinase are key determinants of pathogenesis of Mycobacterium tuberculosis (M. tb). In this study, we found that lysine acetylation plays an important role in the modulation of central carbon metabolism in M. tb. Mutant of M. tb defective in sirtuin deacetylase exhibited improved growth in fatty acid-containing media. Global analysis of lysine acetylome of M. tb identified three acetylated lysine residues (K322, K331, and K392) of isocitrate lyase (ICL1). Using a genetically encoding system, we demonstrated that acetylation of K392 increased the enzyme activity of ICL1, whereas acetylation of K322 decreased its activity. Antibodies that specifically recognized acetyllysine at 392 and 322 of ICL1 were used to monitor the levels of ICL1 acetylation in M. tb cultures. The physiological significance of ICL1 acetylation was demonstrated by the observation that M. tb altered the levels of acetylated K392 in response to changes of carbon sources, and that acetylation of K392 affected the abundance of ICL1 protein. Our study has uncovered another regulatory mechanism of ICL1.
Highlights
Tuberculosis (TB), caused by Mycobacterium tuberculosis (M. tb), continues to be a major global health problem, causing 1.5 million deaths and 9.6 million new infections in 2014
Mutants of M. tb lacking enzymes in central carbon metabolism such as isocitrate lyase and phosphoenolpyruvate carboxykinase were severely attenuated in animal models of infection[14,35]
We have identified a previously unrecognized mechanism which regulates the enzyme activity of ICL1
Summary
Tuberculosis (TB), caused by Mycobacterium tuberculosis (M. tb), continues to be a major global health problem, causing 1.5 million deaths and 9.6 million new infections in 2014. How M. tb survives these harsh conditions has been a subject of intensive research Such knowledge may lead to the development of drugs targeting the latent bacteria. Even-chain-length fatty acids are metabolized by β-oxidation to acetyl-CoA, which is assimilated by the glyoxylate shunt comprising of isocitrate lyase and malate synthase. Increased expression level of isocitrate lyase was observed in M. tb cultures grown under hypoxia[15,16], at low pH17, after macrophage infection[18], and in lung granulomas of TB patients[19], supporting a critical role of isocitrate lyase in M. tb pathogenesis. Lysine acetylation is more prevalent than phosphorylation, and the majority of acetylated proteins are involved in central metabolism and translation, implying an important role in regulation of cellular processes[25,26,27]. We found that lysine acetylation plays a critical role in regulation of central carbon metabolism in M. tb
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