Mycobacterium manipulate glutaminase 1 mediated glutaminolysis to regulate macrophage autophagy for bacteria intracellular survival

Autophagy plays a vital role in eliminating intracellular mycobacterium. It is regulated by multiple metabolic processes including glutaminolysis. Glutaminase 1 (GLS1) is the rate-limiting Enzyme of glutaminolysis and has been reported to control intracellular Gln content. However, its function on regulating Autophagy in mycobacterium infected macrophage is still obscure. Hence, the current study hired mycobacterium virulent strain H37Rv or attenuated strain BCG to infect macrophage and detected the changes in cell glutaminolysis. The function of GLS1 on regulating Autophagy in mycobacterium infected macrophages was further investigated. The results showed that BCG Infection promoted macrophage Autophagy, enhanced glutaminolysis, reduced intracellular Gln content, accompanied with the up-regulation of GLS1. Conversely, H37Rv Infection resulted in completely opposite effects. Meanwhile, knockdown of GLS1 increased Gln content and attenuated Autophagy in BCG infected macrophages. In addition, the deprivation of Gln not only promoted the Autophagy of H37Rv infected macrophages, but also abolished the effect of knockdown GLS1 on regulating BCG infection-induced mTOR activation or Autophagy. To sum up, our study suggested that different virulent strains of mycobacterium Infection have totally opposite effects on glutaminolysis and the expression of GLS1. Specifically, mycobacterium virulent strain reduced GLS1 expression and decreased Gln content but mycobacterium attenuated strain promoted GLS1 expression and enhanced Gln content. Furthermore, GLS1 inhibits the activation of the mTOR signaling pathway and promotes Autophagy by decreasing Gln content.

Autophagy; GLS1;; Glutaminolysis; Macrophage; mycobacterium.