@article{b5e1ee4390a64c36a6772146820e611f,
title = "STING Senses Microbial Viability to Orchestrate Stress-Mediated Autophagy of the Endoplasmic Reticulum",
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.",
keywords = "ER stress, ER-phagy, Gram-positive bacteria, STING, autophagy, c-di-AMP, cell-autonomous innate immunity, mTOR, type-I interferon, vita-PAMP",
author = "Julien Moretti and Soumit Roy and Dominique Bozec and Jennifer Martinez and Chapman, {Jessica R.} and Beatrix Ueberheide and Lamming, {Dudley W.} and Chen, {Zhijian J.} and Tiffany Horng and Garabet Yeretssian and Green, {Douglas R.} and Blander, {J. Magarian}",
note = "Funding Information: We are grateful to I. Dikic, D.M. Sabatini, C. H{\"u}bner, D. Portnoy, C. Roy, R. Vance, J. Woodward, B. Beutler, A. Garcia-Sastre, Z. Yue, and K. Cadwell for bacterial strains, cells, and mice; R. Gordon for electron microscopy, L. Campisi for flow cytometry analyses; Blander lab members and P. Nair-Gupta for discussions; and C. Brou, P. Chastagner, A. Isra{\"e}l, D. Filipescu, D. Kachaner, M. Blander, and S.J. Blander for advice and support. This work was supported by Icahn School of Medicine at Mount Sinai (ISMMS) seed funds to J.M.B. J. Moretti was supported in part by the Philippe Foundation . J. Martinez was supported by the NIH Intramural Research Program ( 1ZIAES10328601 ). D.W.L. was supported by NIH/NIA AG041765 (K99/R00 Pathway to Independence Award) and has received funding from and is a scientific advisory board member of Delos Pharmaceuticals, which seeks to develop novel, selective mTOR inhibitors for the treatment of various diseases. T.H. was supported by the NIH ( AI102964 and AI119763 ). While at ISMMS, G.Y. was supported by The Leona M. and Harry B. Helmsley Charitable Trust (the article does not represent the work, views, or opinions of Helmsley). D.R.G. was supported by the NIH ( AI040646 ) and a Distinguished Investigator Award from the Lupus Research Alliance . J.M.B. and her laboratory by were supported by the NIH ( DK072201 , DK111862 , AI095245 , AI123284 , and AI127658 ), the Burroughs Wellcome Fund , and the Leukemia & Lymphoma Society . The mass spectrometer was supported by NIH/ORIP ( S10OD010582 ). Funding Information: We are grateful to I. Dikic, D.M. Sabatini, C. H?bner, D. Portnoy, C. Roy, R. Vance, J. Woodward, B. Beutler, A. Garcia-Sastre, Z. Yue, and K. Cadwell for bacterial strains, cells, and mice; R. Gordon for electron microscopy, L. Campisi for flow cytometry analyses; Blander lab members and P. Nair-Gupta for discussions; and C. Brou, P. Chastagner, A. Isra?l, D. Filipescu, D. Kachaner, M. Blander, and S.J. Blander for advice and support. This work was supported by Icahn School of Medicine at Mount Sinai (ISMMS) seed funds to J.M.B. J. Moretti was supported in part by the Philippe Foundation. J. Martinez was supported by the NIH Intramural Research Program (1ZIAES10328601). D.W.L. was supported by NIH/NIA AG041765 (K99/R00 Pathway to Independence Award) and has received funding from and is a scientific advisory board member of Delos Pharmaceuticals, which seeks to develop novel, selective mTOR inhibitors for the treatment of various diseases. T.H. was supported by the NIH (AI102964 and AI119763). While at ISMMS, G.Y. was supported by The Leona M. and Harry B. Helmsley Charitable Trust (the article does not represent the work, views, or opinions of Helmsley). D.R.G. was supported by the NIH (AI040646) and a Distinguished Investigator Award from the Lupus Research Alliance. J.M.B. and her laboratory by were supported by the NIH (DK072201, DK111862, AI095245, AI123284, and AI127658), the Burroughs Wellcome Fund, and the Leukemia & Lymphoma Society. The mass spectrometer was supported by NIH/ORIP (S10OD010582). Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2017",
month = nov,
day = "2",
doi = "10.1016/j.cell.2017.09.034",
language = "English (US)",
volume = "171",
pages = "809--823.e13",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "4",
}