Abstract
The innate immune system has evolved to detect molecular signatures associated with invading microbes and the cellular damage these microbes cause. Recognition of microbial genomes, particularly those of intracellular microbes such as viruses, is crucial in triggering a protective response and preventing infection. Many nucleic acid forms are uniquely associated with pathogens (e.g., 5’ppp-RNA, dsRNA) or localize in abnormal cellular compartments during infection (e.g., cytosolic DNA), facilitating the distinction between self and nonself [1]. In particular, the detection of cytosolic DNA has emerged as an important process in infection, as well as cancer, sterile inflammation, and autoimmune diseases such as systemic lupus erythematosus (SLE), in which self-DNA induces type I interferon (IFN) signaling and increases the expression of IFN-stimulated genes (ISGs). Although it has been known for decades that foreign DNA activates potent immune responses [2], only recently have we started to identify the proteins that are responsible for these responses and how they work [3]. A crucial molecule in this process is stimulator of interferon genes (STING), an ER/Golgi-resident protein that recognizes cyclic GMP-AMP (cGAMP), the product of the activated DNA-binding enzyme cGAMP synthase (cGAS). Activation of STING results in a potent transcriptional response involving IFN and multiple inflammatory genes. To ensure that immune responses are proportionate and can eliminate the exogenous challenge without inducing excessive immunopathology, a fine balance between activation and deactivation must be maintained [4]. Writing in Cellular & Molecular Immunology, Hou et al. [5]. revealed how activated STING is delivered for degradation by the autophagic cargo receptor CCDC50, illuminating the mechanisms that control STING turnover and regulate immune responses to infection and chronic autoimmune disease (Fig. 1).