STING Senses Microbial Viability to Orchestrate Stress-Mediated Autophagy of the Endoplasmic Reticulum

Abstract

SUMMARY Constitutive cell-autonomous immunity in metazoans predates interferon-inducible immunity and comprises primordial innate defense. Phagocytes mobilize interferon-inducible responses upon engagement of well-characterized signaling pathways by pathogen-associated molecular patterns (PAMPs). The signals controlling deployment of constitutive cell-autonomous responses during infection have remained elusive. Vita-PAMPs denote microbial viability, signaling the danger of cellular exploitation by intracellular pathogens. We show that cyclic-di-adenosine monophosphate in live Gram-positive bacteria is a vita-PAMP engaging the innate sensor Stimulator of Interferon Genes (STING) to mediate endoplasmic reticulum (ER) stress. Subsequent inactivation of the mechanistic Target of Rapamycin mobilizes autophagy, which sequesters stressed ER membranes, resolves ER stress, and curtails phagocyte death. This vita-PAMP-induced ER-phagy additionally orchestrates an interferon response by localizing ER-resident STING to autophagosomes. Our findings identify stress-mediated ER-phagy as a cell-autonomous response mobilized by STING-dependent sensing of a specific vita-PAMP, and elucidate how innate receptors engage multilayered homeostatic mechanisms to promote immunity and survival after infection.

Emerging lysosomal pathways for quality control at the endoplasmic reticulum

“…An impairment of ER‐phagy or inefficiency in the autophagosomal–lysosomal system is associated with bacterial and viral infection or with conformational diseases, including liver, muscle and neurodegenerative diseases or ageing conditions . In these conditions, misfolded proteins are not efficiently removed from the ER, thus leading to aggregate formation, propagation with disruption of cellular fitness and damage of multiple tissues.…”

At the crossway of ER‐stress and proinflammatory responses

“…Pharmacological disruption of PERK function with the small‐molecule GSK2606414 or indirectly with ISRIB, also greatly reduces inflammatory responses, without compromising ER‐stress‐induced adaptive responses or normal immunological function in the brain . Recently, a constitutive cell‐autonomous phagocyte response specifically to live Gram‐positive bacteria has been delineated . This response aiming at the production of type‐I IFN, is triggered by cyclic‐di‐adenosine monophosphate (c‐di‐AMP), requires STING and is characterized by a multilayered integrated stress response that begins with manifestations of ER‐stress, notably through PERK activation, and culminates in ER‐phagy and heightened cytokine production.…”

Endoplasmic reticulum quality control by garbage disposal

“…Gram‐positive bacteria infected into phagocyte is sensed by STING and causes mTORC1 inactivation‐mediated sequestration of stressed ER membranes. ER‐phagy ameliorates ER stress and mitigates phagocyte death . These findings strongly suggest that ER‐phagy contributes to the removal of damaged ER and the maintenance of ER homeostasis, leading to cell survival and functional recovery.…”