Attenuation of cGAS-STING signaling is mediated by a p62/SQSTM1-dependent autophagy pathway activated by TBK1
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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.
In: The EMBO Journal, Vol. 37, No. 8, e97858, 13.04.2018.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Attenuation of cGAS-STING signaling is mediated by a p62/SQSTM1-dependent autophagy pathway activated by TBK1
AU - Prabakaran, Thaneas
AU - Bodda, Chiranjeevi
AU - Krapp, Christian
AU - Zhang, Bao-Cun
AU - Christensen, Maria H
AU - Sun, Chenglong
AU - Reinert, Line
AU - Cai, Yujia
AU - Jensen, Søren B
AU - Skouboe, Morten K
AU - Nyengaard, Jens R
AU - Thompson, Craig B
AU - Lebbink, Robert Jan
AU - Sen, Ganes C
AU - van Loo, Geert
AU - Nielsen, Rikke
AU - Komatsu, Masaaki
AU - Nejsum, Lene N
AU - Jakobsen, Martin R
AU - Gyrd-Hansen, Mads
AU - Paludan, Søren R
N1 - © 2018 The Authors.
PY - 2018/4/13
Y1 - 2018/4/13
N2 - 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.
AB - 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.
KW - Animals
KW - Autophagy
KW - Cell Line
KW - DNA/metabolism
KW - Humans
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Nucleotidyltransferases/physiology
KW - Protein-Serine-Threonine Kinases/physiology
KW - Sequestosome-1 Protein/physiology
KW - Signal Transduction
U2 - 10.15252/embj.201797858
DO - 10.15252/embj.201797858
M3 - Journal article
C2 - 29496741
VL - 37
JO - E M B O Journal
JF - E M B O Journal
SN - 0261-4189
IS - 8
M1 - e97858
ER -
ID: 280717476