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

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

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

Harvard

Prabakaran, T, Bodda, C, Krapp, C, Zhang, B-C, 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', The EMBO Journal, vol. 37, no. 8, e97858. https://doi.org/10.15252/embj.201797858

APA

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. The EMBO Journal, 37(8), [e97858]. https://doi.org/10.15252/embj.201797858

Vancouver

Prabakaran T, Bodda C, Krapp C, Zhang B-C, Christensen MH, Sun C et al. Attenuation of cGAS-STING signaling is mediated by a p62/SQSTM1-dependent autophagy pathway activated by TBK1. The EMBO Journal. 2018 Apr 13;37(8). e97858. https://doi.org/10.15252/embj.201797858

Author

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. / Attenuation of cGAS-STING signaling is mediated by a p62/SQSTM1-dependent autophagy pathway activated by TBK1. In: The EMBO Journal. 2018 ; Vol. 37, No. 8.

Bibtex

@article{c6769674db6f49dcaf9eb3c8cb829c1c,

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 = "Animals, Autophagy, Cell Line, DNA/metabolism, Humans, Mice, Inbred C57BL, Mice, Knockout, Nucleotidyltransferases/physiology, Protein-Serine-Threonine Kinases/physiology, Sequestosome-1 Protein/physiology, Signal Transduction",

author = "Thaneas Prabakaran and Chiranjeevi Bodda and Christian Krapp and Bao-Cun Zhang 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}",

note = "{\textcopyright} 2018 The Authors.",

year = "2018",

month = apr,

day = "13",

doi = "10.15252/embj.201797858",

language = "English",

volume = "37",

journal = "E M B O Journal",

issn = "0261-4189",

publisher = "Wiley-Blackwell",

number = "8",

}

RIS

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

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

Forskning