Journal
EMBO JOURNAL
Volume 37, Issue 8, Pages -Publisher
WILEY
DOI: 10.15252/embj.201797858
Keywords
autophagy; DNA sensing; innate immunity; p62/SQSTM1; STING
Categories
Funding
- Danish Medical Research Council [12-124330]
- Novo Nordisk Foundation
- Lundbeck Foundation [R198-2015-171, R126-2012-11389]
- Aarhus University Research Foundation
- Villum Foundation
- EU FP7 Mobilex program [4092-00253]
- Chinese Scholarship Council
- graduate School of Health, AU
- Ludwig Institute for Cancer Research Ltd
- Wellcome Trust Fellowship [102894/Z/13/Z]
- Sapere Aude: Danish Council for independent Research Starting Grant
- EMBO Young Investigator Programme
- Lundbeck Foundation [R198-2015-171] Funding Source: researchfish
- Novo Nordisk Fonden [NNF16OC0022084, NNF17OC0027914] Funding Source: researchfish
- Grants-in-Aid for Scientific Research [25111006] Funding Source: KAKEN
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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.
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