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Attenuation of c GAS ‐ STING signaling is mediated by a p62/ SQSTM 1‐dependent autophagy pathway activated by TBK1
Author(s) -
Prabakaran Thaneas,
Bodda Chiranjeevi,
Krapp Christian,
Zhang Baocun,
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,
Loo Geert,
Nielsen Rikke,
Komatsu Masaaki,
Nejsum Lene N,
Jakobsen Martin R,
GyrdHansen Mads,
Paludan Søren R
Publication year - 2018
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201797858
Subject(s) - biology , microbiology and biotechnology , autophagy , signal transduction , sting , genetics , apoptosis , aerospace engineering , engineering
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/ SQSTM 1, which is phosphorylated by TBK 1 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 TBK 1, which phosphorylates IRF 3 to induce IFN expression, but also phosphorylates p62 to stimulate STING degradation and attenuation of the response.