AMPK Promotes Xenophagy through Priming of Autophagic Kinases upon Detection of Bacterial Outer Membrane Vesicles

Abstract

Summary: The autophagy pathway is an essential facet of the innate immune response, capable of rapidly targeting intracellular bacteria. However, the initial signaling regulating autophagy induction in response to pathogens remains largely unclear. Here, we report that AMPK, an upstream activator of the autophagy pathway, is stimulated upon detection of pathogenic bacteria, before bacterial invasion. Bacterial recognition occurs through the detection of outer membrane vesicles. We found that AMPK signaling relieves mTORC1-mediated repression of the autophagy pathway in response to infection, positioning the cell for a rapid induction of autophagy. Moreover, activation of AMPK and inhibition of mTORC1 in response to bacteria is not accompanied by an induction of bulk autophagy. However, AMPK signaling is required for the selective targeting of bacteria-containing vesicles by the autophagy pathway through the activation of pro-autophagic kinase complexes. These results demonstrate a key role for AMPK signaling in coordinating the rapid autophagic response to bacteria. : Autophagy is a degradative process that host cells use to cope with invading pathogens, but its earliest activation is unclear. Losier et al. describe a signaling pathway that is activated by the detection of extracellular bacteria-derived OMVs. This autophagy-initiating pathway results in selective targeting and degradation of bacteria rather than cytoplasmic components. Keywords: autophagy, AMPK, mTOR, ULK1, VPS34, xenophagy, OMV, Salmonella, outer membrane vesicles