Research ArticleHost-Microbe Interactions

β-Barrel outer membrane proteins suppress mTORC2 activation and induce autophagic responses

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Sci. Signal.  27 Nov 2018:
Vol. 11, Issue 558, eaat7493
DOI: 10.1126/scisignal.aat7493

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Barreling over mTORC2

Autophagy can be beneficial for clearing pathogen infection. Gram-negative bacteria commonly have outer membrane proteins with a β-barrel tertiary structure, which is also found in proteins localized to the outer membrane of mitochondria (which are evolutionarily descended from symbiotic bacteria). Chaudhary et al. showed that β-barrel outer membrane proteins were recognized by specific receptors on macrophages and epithelial cells, resulting in suppression of the multiprotein complex mTORC2 and induction of autophagy. Adding outer membrane proteins to mouse macrophages enabled clearance of Salmonella Typhimurium infection. Thus, the signaling pathways activated by outer membrane proteins may contribute to immune responses that promote pathogen clearance or autoimmune diseases.

Abstract

The outer membranes of Gram-negative bacteria and mitochondria contain proteins with a distinct β-barrel tertiary structure that could function as a molecular pattern recognized by the innate immune system. Here, we report that purified outer membrane proteins (OMPs) from different bacterial and mitochondrial sources triggered the induction of autophagy-related endosomal acidification, LC3B lipidation, and p62 degradation. Furthermore, OMPs reduced the phosphorylation and therefore activation of the multiprotein complex mTORC2 and its substrate Akt in macrophages and epithelial cells. The cell surface receptor SlamF8 and the DNA-protein kinase subunit XRCC6 were required for these OMP-specific responses in macrophages and epithelial cells, respectively. The addition of OMPs to mouse bone marrow–derived macrophages infected with Salmonella Typhimurium facilitated bacterial clearance. These data identify a specific cellular response mediated by bacterial and mitochondrial OMPs that can alter inflammatory responses and influence the killing of pathogens.

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