Abstract
The autophagy pathway is an essential facet of theinnate 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.
Highlights
Macroautophagy is a heavily regulated degradative process activated by a range of cellular stressors, including nutrient starvation, proteotoxic aggregates, and pathogen infection (Kaur and Debnath, 2015)
To determine the key upstream signaling events regulating xenophagy induction, we infected colon epithelial cells (HCT116) and bone marrow-derived macrophages (BMDM) with Salmonella and determined the phosphorylation status of established AMPKtarget acetyl-coenzyme A (CoA) carboxylase (ACC) and mTORC1-target ribosomal protein S6 kinase (S6K), which migrates as doublets in some cell lines
Since both epithelial cells and macrophages are capable of inducing xenophagy, this raises the possibility that AMPK activation may be the primary signaling pathway responsible for the activation of the autophagy kinases in the response to infection
Summary
Macroautophagy (hereafter referred to as autophagy) is a heavily regulated degradative process activated by a range of cellular stressors, including nutrient starvation, proteotoxic aggregates, and pathogen infection (Kaur and Debnath, 2015). Recruitment of ULK1 to the site of autophagosome formation (in mammals, this is called the phagophore) is one of the first detectable events in autophagy initiation (Itakura and Mizushima, 2010). Different cellular stressors, including nutrient starvation, ROS (reactive oxygen species) accumulation, and reduced cytokine signaling, are capable of activating autophagy by shifting the balance of activating and inhibitory phosphorylation of ULK1 by mTORC1 and AMPK (Russell et al, 2014). AMPK and mTORC1 have been described as directly regulating the activity of the VPS34 kinases, ensuring a tightly controlled burst of autophagy initiation in response to cellular stresses and underscoring the importance of VPS34 regulation (Yuan et al, 2013; Kim et al, 2013)
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