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

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Salmonella enterica is a food- and water-borne pathogen that has evolved closely with vertebrate hosts. Two medically relevant serovars include S. typhimurium, which causes gastroenteritis and S. typhi, which is the causative agent of typhoid fever. Host cells can utilize a process called autophagy, normally involved in the elimination of defective proteins and organelles, to capture and degrade intracellular pathogens. Enteric Salmonella express numerous virulence factors that enable the bacterium to subvert host defense mechanisms. Here we report that Salmonella specifically activates the host molecule focal adhesion kinase (FAK) in macrophages, triggering a signaling cascade that suppresses the autophagic elimination of intracellular bacteria. A key regulator of autophagy in mammalian cells is the target of rapamycin, mTOR, which transmits inhibitory signals that downregulate the autophagic response. We show that Salmonella-induced FAK activation leads to the Akt-dependent activation of mTOR, thereby repressing autophagic signaling. Inhibition of autophagy results in increased bacterial survival, while in FAK-deficient cells, autophagy is enhanced and intracellular Salmonella are eliminated. We also show that in mice lacking macrophage-specific FAK, animals were less susceptible to oral Salmonella infection. Together, these data identify FAK as a novel regulator of autophagy in macrophages with broad implications for host survival.

Vyšlo v časopise: Activation of Focal Adhesion Kinase by Suppresses Autophagy via an Akt/mTOR Signaling Pathway and Promotes Bacterial Survival in Macrophages. PLoS Pathog 10(6): e32767. doi:10.1371/journal.ppat.1004159
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004159

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