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

Thaneas Prabakaran; Chiranjeevi Bodda; Christian Krapp; Bao Cun Zhang; Maria H. Christensen; Chenglong Sun; Line Reinert; Yujia Cai; Søren B. Jensen; Morten K. Skouboe; Jens R. Nyengaard; Craig B. Thompson; Robert Jan Lebbink; Ganes C. Sen; Geert van Loo; Rikke Nielsen; Masaaki Komatsu; Lene N. Nejsum; Martin R. Jakobsen; Mads Gyrd-Hansen; Søren R. Paludan

doi:10.15252/embj.201797858

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

Thaneas Prabakaran, Chiranjeevi Bodda, Christian Krapp, Bao Cun Zhang, Maria H. Christensen, Chenglong Sun, Line Reinert, Yujia Cai, Søren B. Jensen, Morten K. Skouboe, Jens R. Nyengaard, Craig B. Thompson, Robert Jan Lebbink, Ganes C. Sen, Geert van Loo, Rikke Nielsen, Masaaki Komatsu, Lene N. Nejsum, Martin R. Jakobsen, Mads Gyrd-HansenSøren R. Paludan

Research output: Contribution to journal › Article › peer-review

261 Scopus citations

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.

Original language	English (US)
Article number	e97858
Journal	EMBO Journal
Volume	37
Issue number	8
DOIs	https://doi.org/10.15252/embj.201797858
State	Published - Apr 13 2018
Externally published	Yes

Keywords

DNA sensing
STING
autophagy
innate immunity
p62/SQSTM1

ASJC Scopus subject areas

General Neuroscience
Molecular Biology
General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology

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10.15252/embj.201797858

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Prabakaran, T., Bodda, C., Krapp, C., Zhang, B. C., Christensen, M. H., Sun, C., Reinert, L., Cai, Y., Jensen, S. B., Skouboe, M. K., Nyengaard, J. R., Thompson, C. B., Lebbink, R. J., Sen, G. C., van Loo, G., Nielsen, R., Komatsu, M., Nejsum, L. N., Jakobsen, M. R., ... Paludan, S. R. (2018). Attenuation of cGAS-STING signaling is mediated by a p62/SQSTM1-dependent autophagy pathway activated by TBK1. EMBO Journal, 37(8), Article e97858. https://doi.org/10.15252/embj.201797858

Prabakaran, T, Bodda, C, Krapp, C, Zhang, BC, Christensen, MH, Sun, C, Reinert, L, Cai, Y, Jensen, SB, Skouboe, MK, Nyengaard, JR, Thompson, CB, Lebbink, RJ, Sen, GC, van Loo, G, Nielsen, R, Komatsu, M, Nejsum, LN, Jakobsen, MR, Gyrd-Hansen, M & Paludan, SR 2018, 'Attenuation of cGAS-STING signaling is mediated by a p62/SQSTM1-dependent autophagy pathway activated by TBK1', EMBO Journal, vol. 37, no. 8, e97858. https://doi.org/10.15252/embj.201797858

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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.}",

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year = "2018",

month = apr,

day = "13",

doi = "10.15252/embj.201797858",

language = "English (US)",

volume = "37",

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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.

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 - DNA sensing

KW - STING

KW - autophagy

KW - innate immunity

KW - p62/SQSTM1

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ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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