Activation of Focal Adhesion Kinase by Salmonella Suppresses Autophagy via an Akt/mTOR Signaling Pathway and Promotes Bacterial Survival in Macrophages

PLoS Pathogens

Katherine A. Owen¹  James E. Casanova¹  Corey B. Meyer¹  Amy H. Bouton² 

[1] Department of Cell Biology, University of Virginia Health System, Charlottesville, Virginia, United States of America;Department of Microbiology, University of Virginia Health System, Charlottesville, Virginia, United States of America

关键词: Salmonella;    Macrophages;    Salmonella typhimurium;    Autophagic cell death;    Salmonellosis;    Intracellular pathogens;    Immunoblotting;    Secretion systems;   

DOI  :  10.1371/journal.ppat.1004159

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Autophagy has emerged as an important antimicrobial host defense mechanism that not only orchestrates the systemic immune response, but also functions in a cell autonomous manner to directly eliminate invading pathogens. Pathogenic bacteria such as Salmonella have evolved adaptations to protect themselves from autophagic elimination. Here we show that signaling through the non-receptor tyrosine kinase focal adhesion kinase (FAK) is actively manipulated by the Salmonella SPI-2 system in macrophages to promote intracellular survival. In wild-type macrophages, FAK is recruited to the surface of the Salmonella-containing vacuole (SCV), leading to amplified signaling through the Akt-mTOR axis and inhibition of the autophagic response. In FAK-deficient macrophages, Akt/mTOR signaling is attenuated and autophagic capture of intracellular bacteria is enhanced, resulting in reduced bacterial survival. We further demonstrate that enhanced autophagy in FAK−/− macrophages requires the activity of Atg5 and ULK1 in a process that is distinct from LC3-assisted phagocytosis (LAP). In vivo, selective knockout of FAK in macrophages resulted in more rapid clearance of bacteria from tissues after oral infection with S. typhimurium. Clearance was correlated with reduced infiltration of inflammatory cell types into infected tissues and reduced tissue damage. Together, these data demonstrate that FAK is specifically targeted by S. typhimurium as a novel means of suppressing autophagy in macrophages, thereby enhancing their intracellular survival.

【 授权许可】

CC BY