Title | Pro-inflammation Associated with a Gain-of-Function Mutation (R284S) in the Innate Immune Sensor STING. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Konno, H, Chinn, IK, Hong, D, Orange, JS, Lupski, JR, Mendoza, A, Pedroza, LA, Barber, GN |
Journal | Cell Rep |
Volume | 23 |
Issue | 4 |
Pagination | 1112-1123 |
Date Published | 2018 Apr 24 |
ISSN | 2211-1247 |
Keywords | Animals, Autophagy, Autophagy-Related Protein-1 Homolog, Gain of Function Mutation, HEK293 Cells, Humans, Inflammation, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Mice, Mice, Knockout |
Abstract | 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. |
DOI | 10.1016/j.celrep.2018.03.115 |
Alternate Journal | Cell Rep |
PubMed ID | 29694889 |
PubMed Central ID | PMC6092751 |
Grant List | R01 AI079336 / AI / NIAID NIH HHS / United States R01 CA095924 / CA / NCI NIH HHS / United States R01 CA194404 / CA / NCI NIH HHS / United States UM1 HG006542 / HG / NHGRI NIH HHS / United States |
Pro-inflammation Associated with a Gain-of-Function Mutation (R284S) in the Innate Immune Sensor STING.
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