@article{b946b354941b41fba9b26bb97040bb1d,
title = "Attenuation of cGAS-STING signaling is mediated by a p62/SQSTM1-dependent autophagy pathway activated by TBK1",
abstract = "Negative regulation of immune pathways is essential to achieve resolution of immune responses and to avoid excess inflammation. DNA stimulates type I IFN expression through the DNA sensor cGAS, the second messenger cGAMP, and the adaptor molecule STING. Here, we report that STING degradation following activation of the pathway occurs through autophagy and is mediated by p62/SQSTM1, which is phosphorylated by TBK1 to direct ubiquitinated STING to autophagosomes. Degradation of STING was impaired in p62-deficient cells, which responded with elevated IFN production to foreign DNA and DNA pathogens. In the absence of p62, STING failed to traffic to autophagy-associated vesicles. Thus, DNA sensing induces the cGAS-STING pathway to activate TBK1, which phosphorylates IRF3 to induce IFN expression, but also phosphorylates p62 to stimulate STING degradation and attenuation of the response.",
keywords = "DNA sensing, STING, autophagy, innate immunity, p62/SQSTM1",
author = "Thaneas Prabakaran and Chiranjeevi Bodda and Christian Krapp and Zhang, {Bao Cun} and Christensen, {Maria H.} and Chenglong Sun and Line Reinert and Yujia Cai and Jensen, {S{\o}ren B.} and Skouboe, {Morten K.} and Nyengaard, {Jens R.} and Thompson, {Craig B.} and Lebbink, {Robert Jan} and Sen, {Ganes C.} and {van Loo}, Geert and Rikke Nielsen and Masaaki Komatsu and Nejsum, {Lene N.} and Jakobsen, {Martin R.} and Mads Gyrd-Hansen and Paludan, {S{\o}ren R.}",
note = "Funding Information: The technical assistance of Kirsten Stadel Petersen, Gitte Albinus Pedersen, and Ane Kjeldsen is greatly appreciated. This work was funded by The Danish Medical Research Council (12-124330), The Novo Nordisk Foundation, The Lundbeck Foundation (R198-2015-171), and Aarhus University Research Foundation (all S.R.P.). Centre for Stochastic Geometry and Advanced Bioimaging is supported by the Villum Foundation. In addition, we received funding from The Lundbeck Foundation (R126-2012-11389, T.P.), The EU FP7 Mobilex program (4092-00253) (C.B.), The Chinese Scholarship Council (C.S.), and The graduate School of Health, AU (M.H.C.). M.G-H. is supported by Ludwig Institute for Cancer Research Ltd, a Wellcome Trust Fellowship (102894/Z/13/Z), a Sapere Aude: Danish Council for independent Research Starting Grant, and the EMBO Young Investigator Programme. Publisher Copyright: {\textcopyright} 2018 The Authors",
year = "2018",
month = apr,
day = "13",
doi = "10.15252/embj.201797858",
language = "English (US)",
volume = "37",
journal = "EMBO Journal",
issn = "0261-4189",
publisher = "Nature Publishing Group",
number = "8",
}