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

Julien Moretti, Soumit Roy, Dominique Bozec, Jennifer Martinez, Jessica R. Chapman, Beatrix Ueberheide, Dudley W. Lamming, Zhijian J. Chen, Tiffany Horng, Garabet Yeretssian, Douglas R. Green, J. Magarian Blander

Research output: Contribution to journalArticle

94 Scopus citations

Abstract

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. Detection of live bacteria through STING triggers ER-phagy and resolution of cellular stress, allowing cells to deal with the threat and remain viable and functional.

Original languageEnglish (US)
Pages (from-to)809-823.e13
JournalCell
Volume171
Issue number4
DOIs
StatePublished - Nov 2 2017

Keywords

  • ER stress
  • ER-phagy
  • Gram-positive bacteria
  • STING
  • autophagy
  • c-di-AMP
  • cell-autonomous innate immunity
  • mTOR
  • type-I interferon
  • vita-PAMP

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Moretti, J., Roy, S., Bozec, D., Martinez, J., Chapman, J. R., Ueberheide, B., Lamming, D. W., Chen, Z. J., Horng, T., Yeretssian, G., Green, D. R., & Blander, J. M. (2017). STING Senses Microbial Viability to Orchestrate Stress-Mediated Autophagy of the Endoplasmic Reticulum. Cell, 171(4), 809-823.e13. https://doi.org/10.1016/j.cell.2017.09.034