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

TitlePro-inflammation Associated with a Gain-of-Function Mutation (R284S) in the Innate Immune Sensor STING.
Publication TypeJournal Article
Year of Publication2018
AuthorsKonno, H, Chinn, IK, Hong, D, Orange, JS, Lupski, JR, Mendoza, A, Pedroza, LA, Barber, GN
JournalCell Rep
Volume23
Issue4
Pagination1112-1123
Date Published2018 Apr 24
ISSN2211-1247
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.

DOI10.1016/j.celrep.2018.03.115
Alternate JournalCell Rep
PubMed ID29694889
Grant ListUM1 HG006542 / HG / NHGRI NIH HHS / United States