Attenuation of cGAS-STING signaling is mediated by a p62/SQSTM1-dependent autophagy pathway activated by TBK1
Prabakaran, Thaneas; Bodda, Chiranjeevi; Krapp, Christian; Zhang, Bao-Cun; Christensen, Maria H; Sun, Chenglong; Reinert, Line; Cai, Yujia; Jensen, Søren B; Skouboe, Morten K; Nyengaard, Jens R; Thompson, Craig B; Lebbink, Robert Jan; Sen, Ganes C; van Loo, Geert; Nielsen, Rikke; Komatsu, Masaaki; Nejsum, Lene N; Jakobsen, Martin R; Gyrd-Hansen, Mads; Paludan, Søren R
(2018) EMBO Journal, volume 37, issue 8
(Article)
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
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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.
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Keywords: DNA sensing, STING, autophagy, innate immunity, p62/SQSTM1, General Biochemistry,Genetics and Molecular Biology, General Immunology and Microbiology, Molecular Biology, General Neuroscience
ISSN: 0261-4189
Publisher: Nature Publishing Group
Note: Publisher Copyright: © 2018 The Authors
(Peer reviewed)