Salmonella Typhimurium disrupts Sirt1/AMPK checkpoint control of mTOR to impair autophagy

During intracellular infections, autophagy significantly contributes to the elimination of pathogens, regulation of pro-inflammatory signaling, secretion of immune mediators and in coordinating the adaptive immune system. Intracellular pathogens such as S . Typhimurium have evolved mechanisms to circumvent autophagy. However, the regulatory mechanisms targeted by S . Typhimurium to modulate autophagy have not been fully resolved. Here we report that cytosolic energy loss during S . Typhimurium infection triggers transient activation of AMPK, an important checkpoint of mTOR activity and autophagy. The activation of AMPK is regulated by LKB1 in a cytosolic complex containing Sirt1 and LKB1, where Sirt1 is required for deacetylation and subsequent activation of LKB1. S . Typhimurium infection targets Sirt1, LKB1 and AMPK to lysosomes for rapid degradation resulting in the disruption of the AMPK-mediated regulation of mTOR and autophagy. The degradation of cytosolic Sirt1/LKB1/AMPK complex was not observed with two mutant strains of S . Typhimurium, ΔssrB and ΔssaV , both compromising the pathogenicity island 2 (SPI2). The results highlight virulence factor-dependent degradation of host cell proteins as a previously unrecognized strategy of S . Typhimurium to evade autophagy.