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

Abstract

<p id="d5247523e649">Negative regulation of immune pathways is essential to achieve resolution of immune responses and to avoid excess inflammation. <span style="fixed-case">DNA</span> stimulates type I <span style="fixed-case">IFN</span> expression through the <span style="fixed-case">DNA</span> sensor <span style="fixed-case">cGAS</span>, the second messenger <span style="fixed-case">cGAMP</span>, and the adaptor molecule <span style="fixed-case">STING</span>. Here, we report that <span style="fixed-case">STING</span> degradation following activation of the pathway occurs through autophagy and is mediated by p62/ <span style="fixed-case">SQSTM</span>1, which is phosphorylated by <span style="fixed-case">TBK</span>1 to direct ubiquitinated <span style="fixed-case">STING</span> to autophagosomes. Degradation of <span style="fixed-case">STING</span> was impaired in p62‐deficient cells, which responded with elevated <span style="fixed-case">IFN</span> production to foreign <span style="fixed-case">DNA</span> and <span style="fixed-case">DNA</span> pathogens. In the absence of p62, <span style="fixed-case">STING</span> failed to traffic to autophagy‐associated vesicles. Thus, <span style="fixed-case">DNA</span> sensing induces the <span style="fixed-case">cGAS</span>‐ <span style="fixed-case">STING</span> pathway to activate <span style="fixed-case">TBK</span>1, which phosphorylates <span style="fixed-case">IRF</span>3 to induce <span style="fixed-case">IFN</span> expression, but also phosphorylates p62 to stimulate <span style="fixed-case">STING</span> degradation and attenuation of the response. </p>