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Attenuation of cGAS-STING signaling is mediated by a p62/SQSTM1-dependent autophagy pathway activated by TBK1

(2018) EMBO JOURNAL. 37(8).
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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
E3 UBIQUITIN LIGASE, GMP-AMP SYNTHASE, IMMUNE-RESPONSES, DNA SENSOR, LISTERIA-MONOCYTOGENES, SELECTIVE AUTOPHAGY, ANTIVIRAL RESPONSE, IMMUNOGENIC TUMORS, INTRACELLULAR DNA, TUBERCULOSIS DNA, autophagy, DNA sensing, innate immunity, p62/SQSTM1, STING

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Citation

Please use this url to cite or link to this publication:

Chicago
Prabakaran, Thaneas, Chiranjeevi Bodda, Christian Krapp, Bao-cun Zhang, Maria H Christensen, Chenglong Sun, Line Reinert, et al. 2018. “Attenuation of cGAS-STING Signaling Is Mediated by a p62/SQSTM1-dependent Autophagy Pathway Activated by TBK1.” Embo Journal 37 (8).
APA
Prabakaran, T., Bodda, C., Krapp, C., Zhang, B., Christensen, M. H., Sun, C., Reinert, L., et al. (2018). Attenuation of cGAS-STING signaling is mediated by a p62/SQSTM1-dependent autophagy pathway activated by TBK1. EMBO JOURNAL, 37(8).
Vancouver
1.
Prabakaran T, Bodda C, Krapp C, Zhang B, Christensen MH, Sun C, et al. Attenuation of cGAS-STING signaling is mediated by a p62/SQSTM1-dependent autophagy pathway activated by TBK1. EMBO JOURNAL. 2018;37(8).
MLA
Prabakaran, Thaneas, Chiranjeevi Bodda, Christian Krapp, et al. “Attenuation of cGAS-STING Signaling Is Mediated by a p62/SQSTM1-dependent Autophagy Pathway Activated by TBK1.” EMBO JOURNAL 37.8 (2018): n. pag. Print.
@article{8561178,
  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.},
  articleno    = {e97858},
  author       = {Prabakaran, Thaneas and Bodda, Chiranjeevi and Krapp, Christian and Zhang, Bao-cun and Christensen, Maria H and Sun, Chenglong and Reinert, Line and Cai, Yujia and Jensen, Soren 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 Nielsen, Rikke and Komatsu, Masaaki and Nejsum, Lene N and Jakobsen, Martin R and Gyrd-Hansen, Mads and Paludan, Soren R},
  issn         = {0261-4189},
  journal      = {EMBO JOURNAL},
  language     = {eng},
  number       = {8},
  pages        = {17},
  title        = {Attenuation of cGAS-STING signaling is mediated by a p62/SQSTM1-dependent autophagy pathway activated by TBK1},
  url          = {http://dx.doi.org/10.15252/embj.201797858},
  volume       = {37},
  year         = {2018},
}

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