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

Abstract

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.

Effects of sea horse (Hippocampus abdominalis)-derived protein hydrolysate on skeletal muscle development

“…Upon stimulation, AKT, a regulator of glucose homeostatis, phosphorylates mTOR thereby increasing muscle protein synthesis and muscle hypertrophy, as a result of which increase in muscle mass is expected. Further, Phosphorylated AKT is said to induce lysosomal degradation of SIRT1 by translocating it to the cytosolic region from the nucleus, by which antioxidant property of the cell is enhanced (Raja et al 2017). Previous reports states that, AKT, in addition to mTOR, phosphorylates wide range of proteins that includes FOXO.…”

A role for the Salmonella Type III Secretion System 1 in bacterial adaptation to the cytosol of epithelial cells

“…Specifically, bacteria are subject to a variation of autophagy known as xenophagy, an evolutionarily conserved mechanism, which controls Salmonella replication (Birmingham et al , ; Jia et al , ; Benjamin et al , ; Conway et al , ). The autophagic response to Salmonella is transient and occurs early during infection (Tattoli et al , ; Ganesan et al , ). We found that expression of SipA during this early phase was required for optimal intracellular proliferation and, furthermore, that the requirement for SipA was dependent on autophagy.…”

Toll‐like receptor signalling cross‐activates the autophagic pathway to restrictSalmonellaTyphimurium growth in macrophages

“…ULK1 phosphorylation and activation lead to autophagy induction (Alers et al, ; Russell et al, ; Wong et al, ). Ganesan et al () reported that S . Typhimurium SL1344 strain invades mouse bone marrow‐derived macrophages, the rupture of cell membranes and subsequent decrease of intracellular ATP levels lead to transient AMPK activation that occurs at 1 hr post infection.…”

“…These observations suggest that Salmonella can subvert autophagy by degrading AMPK activation and subsequently mTOR activation to evade host cell defences against the invading intracellular pathogens. But the question whether AMPK degradation leads to decreased ULK1 S555 and increased ULK1 S757 phosphorylation was not studied (Ganesan et al, ). Our present study demonstrated that S .…”