Pro-inflammation Associated with a Gain-of-Function Mutation (R284S) in the Innate Immune Sensor STING

• Published in: Cell reports (Cambridge) Vol. 23; no. 4; pp. 1112 - 1123
• Main Authors: Konno, Hiroyasu, Chinn, Ivan K., Hong, Diana, Orange, Jordan S., Lupski, James R., Mendoza, Alejandra, Pedroza, Luis A., Barber, Glen N.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.04.2018; Elsevier
• Subjects: AMPK inhibitor; Animals; autoimmune disease; Autophagy - genetics; Autophagy - immunology; Autophagy-Related Protein-1 Homolog - genetics; Autophagy-Related Protein-1 Homolog - immunology; Gain of Function Mutation; HEK293 Cells; Humans; Inflammation - genetics; Inflammation - immunology; Inflammation - pathology; inflammatory disease; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - immunology; Membrane Proteins - genetics; Membrane Proteins - immunology; Mice; Mice, Knockout; STING; STING inhibitor; type I interferonopathy; ULK1 phosphorylation; gain-of-function mutation; inflammatory disease; AMPK inhibitor; STING; type I interferonopathy; STING inhibitor; ULK1 phosphorylation; autoimmune disease
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.03.115

The cellular sensor stimulator of interferon genes (STING) initiates type I interferon (IFN) and cytokine production following association with cyclic dinucleotides (CDNs) generated from intracellular bacteria or via a cellular synthase, cGAS, after binding microbial or self-DNA. Although essential for protecting the host against infection, unscheduled STING signaling is now known to be responsible for a variety of autoinflammatory disorders. Here, we report a gain-of-function mutation in STING (R284S), isolated from a patient who did not require CDNs to augment activity and who manifested a constitutively active phenotype. Control of the Unc-51-like autophagy activating kinase 1 (ULK1) pathway, which has previously been shown to influence STING function, was potently able to suppress STING (R284S) activity to alleviate cytokine production. Our findings add to the growing list of inflammatory syndromes associated with spontaneous STING signaling and provide a therapeutic strategy for the treatment of STING-induced inflammatory disease. [Display omitted] •A single nucleotide change in the STING gene generates an active STING variant•STING (R284S) is active in the absence of cyclic dinucleotides•ULK1 phosphorylation of STING can inhibit STING-dependent cytokine production•AMPK/ULK1 regulators may be useful to treat STING-related inflammatory disease Konno et al. characterize a gain-of-function mutation in the innate immune sensor STING isolated from a patient. AMPK/ULK1 regulators are able to repress constitutive STING signaling, suggesting a possible therapeutic approach for the treatment of STING-related inflammatory disease.