Detection of a vita-PAMP STINGs cells into reticulophagy.

Phagocytes cope with the threat of living bacteria via detection of vita-PAMPs, a specific class of pathogen-associated molecular patterns (PAMPs) that denotes microbial viability and trigger a commensurate innate response. Prokaryotic mRNA and cyclic-di-adenosine monophosphate (c-di-AMP) serve as vita-PAMPs for Gram-negative and Gram-positive bacteria, respectively, and elicit heightened proinflammatory responses not warranted for dead bacteria. The innate sensor TMEM173/STING detects c-di-AMP produced by internalized live Gram-positive bacteria, and quickly mobilizes interdependent pre-formed cell-autonomous responses including endoplasmic reticulum (ER) stress, MTOR inactivation, and reticulophagy. In turn, reticulophagy serves a dual role in restoring phagocyte homeostasis and orchestrating a type I IFN response. ER-stress induced macroautophagy/autophagy sequesters stressed ER, resolves ER stress and prevents apoptosis in response to live bacteria. Reticulophagy relocalizes ER-resident TMEM173/STING to phagophores, which then act as TMEM173/STING-signaling compartments. Here, we discuss our findings in the context of innate immunity and cell homeostasis.