Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
Veterans Administration Long Beach Health Care System and University of California at Irvine, Irvine, CA, USA.
EMBO Rep. 2021 Feb 3;22(2):e50613. doi: 10.15252/embr.202050613. Epub 2020 Dec 20.
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.
导致铜绿假单胞菌毒力的一个主要因素是其能够在气道上皮细胞内不受挑战地生存和复制。铜绿假单胞菌逃避细胞内宿主防御机制（如自噬）破坏的机制尚不清楚。在这里，我们表明 III 型分泌系统效应蛋白 ExoS 通过抑制宿主细胞中的自噬来促进铜绿假单胞菌在气道上皮细胞中的存活。自噬抑制不依赖于 mTOR 活性，因为后者也被 ExoS 抑制，尽管机制不同。气道上皮细胞中关键自噬基因 Atg7 的缺失，无论是在体外还是在小鼠模型中，都极大地增强了 ExoS 缺失铜绿假单胞菌的存活，但并不影响 ExoS 含菌的存活。ExoS 对自噬和 mTOR 的抑制作用依赖于其 ADP-核糖基转移酶结构域的活性。ExoS 介导的 RAS ADP 核糖基化导致 mTOR 抑制，而自噬抑制则归因于自噬 Vps34 激酶活性的抑制。
