RegX3 Controls Glyoxylate Shunt and Mycobacteria Survival by Directly Regulating the Transcription of Isocitrate Lyase Gene in Mycobacterium smegmatis

Abstract

The glyoxylate shunt is a pathway associated with the assimilation of fatty acids and is implicated in the resistance of M. tuberculosis (Mtb). Isocitrate lyase (ICL), the first enzyme in the glyoxylate shunt, mediates Mtb infections and its survival in mice via fatty acids, metabolism, and physiological functions. Here, we found that in Mycobacterium smegmatis (M. smegmatis) the two-component system SenX3-RegX3 regulated the glyoxylate shunt in response to phosphate starvation by controlling the transcription of icl. In response to phosphate availability, the phosphate regulator RegX3 directly bound to the upstream regulatory region of icl and repressed its transcription. The inactivation of regX3 increased icl transcription and ICL activity, causing a growth defect in M. smegmatis with fatty acids as the sole source of carbon and energy. The growth defect was partly due to the toxicity of the excess glyoxylate produced by ICL. A decrease in glyoxylic acid levels, overexpression of regX3, or the chemical inhibition (IA or 3-NP) of ICL restored the growth of the Regx3-deficient M. smegmatis. Thus, we established a genetic network between the phosphate stress response and glyoxylate shunt based on the amount of intracellular ICL during mycobacterial survival on short-chain fatty acids, which contributed to its antimicrobial arsenal.

The Pan-Genomic Analysis of Corynebacterium striatum Revealed its Genetic Characteristics as an Emerging Multidrug-Resistant Pathogen

“… 69 The regX3 gene, which encodes a sensory transduction protein, was identified in 89.8% of the strains. 70 Interestingly, isolates from different geographical locations and tissues did not show significant differences in virulence factors.…”

GATA-type transcriptional factor SpGAT1 interacts with SpMIG1 and promotes lipid accumulation in the oleaginous yeast $$Saitozyma \ podzolica$$ zwy-2-3

“…In oleaginous yeast, the more lipid accumulated, the more lipid degraded, relatively; and the consumption of fatty acids required the regulation of the carbon flux bifurcation between the TCA cycle and the glyoxylate shunt. In this context, the glyoxylate shunt was significantly up-regulated to maintain the TCA cycle [ 46 , 50 ]. Therefore, SpGAT1 may positively regulate ICL 1 and ICL 2 to speed up the TCA cycle and accelerated citric acid storage in the cytoplasm, which could return to raise cytoplasmic acetyl-CoA levels in zwy-2-3 [ 51 – 53 ].…”

Protein acylation links metabolism and the control of signal transduction, transcription regulation, growth, and pathogenicity in Actinobacteria

“…Intracellular survival within macrophages, which are thought to provide a nutritionally restricted environment, is important for mycobacterial pathogenesis. The survival of M. tuberculosis in macrophages was discovered to be involved in cholesterol degradation (VanderVen et al, 2015; Xu et al, 2021). Although the mechanisms by which M. tuberculosis persists in macrophages remain largely unknown, the degradation products of cholesterol, including acetyl‐CoA, propionyl‐CoA, and succinyl‐CoA, are good targets for understanding the pathogenesis of mycobacteria.…”