Cell 171, 809–823 (2017)

Cyclic-di-adenosine monophosphate (c-di-AMP) is a bacterial second messenger that induces the interferon response through the innate sensor stimulator of interferon genes (STING). Innate immune system discrimination between self and non-self depends on pathogen-associated molecular pattern (PAMP) recognition. Microorganisms signal viability through vita-PAMPs present in live, but not dead, microorganisms. However vita-PAMPs and the responses they induce are not well defined.

Blander and colleagues identify c-di-AMP as a vita-PAMP that induces STING-dependent endoplasmic reticulum (ER) stress to protect mice against bacterial infection through inactivation of mTOR and induction of autophagy.

The authors studied phagocyte responses to avirulent Gram-positive Listeria innocua and found that live, but not dead bacteria induced autophagy by inactivating mTORC1. Live bacteria elicited an ER stress response critical for defence against infection, and autophagy inhibition sustained ER stress and induced cell death following infection. Fractionation experiments indicated ER-stress-mediated autophagy sequesters stressed ER membranes. A quantitative mass spectrometry approach identified STING as enriched in autophagosomes during the bacterial response. The authors then uncovered how STING senses c-di-AMP as a vita-PAMP to induce autophagy and interferon response.

This elegant work links immune signalling and autophagy in a mechanism that allows cells to respond to threats and survive infection by maintaining homeostasis.