Pseudomonas aeruginosa survives in epithelia by ExoS‐mediated inhibition of autophagy and mTOR |
| |
| Authors: | Lang Rao Indhira De La Rosa Yi Xu Youbao Sha Abhisek Bhattacharya Michael J Holtzman Brian E Gilbert N Tony Eissa |
| |
| Institution: | 1. Department of Medicine, Baylor College of Medicine, Houston TX, USA ; 2. Veterans Administration Long Beach Health Care System and University of California at Irvine, Irvine CA, USA ; 3. Southern California Institute for Research and Education, Long Beach CA, USA ; 4. Department of Internal Medicine, Washington University School of Medicine, St. Louis MO, USA ; 5. Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston TX, USA |
| |
| Abstract: | One major factor that contributes to the virulence of Pseudomonas aeruginosa is its ability to reside and replicate unchallenged inside airway epithelial cells. The mechanism by which P. aeruginosa escapes destruction by intracellular host defense mechanisms, such as autophagy, is not known. Here, we show that the type III secretion system effector protein ExoS facilitates P. aeruginosa survival in airway epithelial cells by inhibiting autophagy in host cells. Autophagy inhibition is independent of mTOR activity, as the latter is also inhibited by ExoS, albeit by a different mechanism. Deficiency of the critical autophagy gene Atg7 in airway epithelial cells, both in vitro and in mouse models, greatly enhances the survival of ExoS‐deficient P. aeruginosa but does not affect the survival of ExoS‐containing bacteria. The inhibitory effect of ExoS on autophagy and mTOR depends on the activity of its ADP‐ribosyltransferase domain. Inhibition of mTOR is caused by ExoS‐mediated ADP ribosylation of RAS, whereas autophagy inhibition is due to the suppression of autophagic Vps34 kinase activity. |
| |
| Keywords: | ADP‐ ribosyltransferase autophagy ExoS mTOR Pseudomonas aeruginosa |
|
|
