2. Academic Validation
  3. Attenuation of cGAS-STING signaling is mediated by a p62/SQSTM1-dependent autophagy pathway activated by TBK1

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

  • EMBO J. 2018 Apr 13;37(8):e97858. doi: 10.15252/embj.201797858.
Thaneas Prabakaran 1 2,  Chiranjeevi Bodda 1 2 3,  Christian Krapp 1 2,  Bao-Cun Zhang 1 2,  Maria H Christensen 1 2,  Chenglong Sun 1 2,  Line Reinert 1 2,  Yujia Cai 1 2,  Søren B Jensen 1 2,  Morten K Skouboe 1 2,  Jens R Nyengaard 4,  Craig B Thompson 5,  Robert Jan Lebbink 6,  Ganes C Sen 7,  Geert van Loo 8 9,  Rikke Nielsen 1,  Masaaki Komatsu 10,  Lene N Nejsum 4,  Martin R Jakobsen 1 2,  Mads Gyrd-Hansen 3,  Søren R Paludan 11 2
Affiliations

Affiliations

  • 1 Department of Biomedicine, Aarhus University, Aarhus, Denmark.
  • 2 Aarhus Research Center for Innate Immunity, Aarhus University, Aarhus, Denmark.
  • 3 Nuffield Department of Medicine, Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK.
  • 4 Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
  • 5 Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 6 Medical Microbiology, University Medical Center, Utrecht, The Netherlands.
  • 7 Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
  • 8 Inflammation Research Center, VIB, Ghent, Belgium.
  • 9 Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
  • 10 Department of Biochemistry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
  • 11 Department of Biomedicine, Aarhus University, Aarhus, Denmark [email protected].
PMID: 29496741 DOI: 10.15252/embj.201797858
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

STING; DNA sensing; autophagy; innate immunity; p62/SQSTM1.

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