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Cell Rep. 2018 Apr 24;23(4):1112-1123. doi: 10.1016/j.celrep.2018.03.115.

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

Author information

1
Department of Cell Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
2
Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Division of Immunology/Allergy/Rheumatology, Texas Children's Hospital, Houston, TX 77030, USA; Center for Human Immunobiology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX 77030, USA.
3
Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
4
Colegio de Ciencias de la Salud-Hospital de los Valles, Universidad San Francisco de Quito, Quito, Ecuador.
5
Department of Cell Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA. Electronic address: gbarber@med.miami.edu.

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.

KEYWORDS:

AMPK inhibitor; STING; STING inhibitor; ULK1 phosphorylation; autoimmune disease; gain-of-function mutation; inflammatory disease; type I interferonopathy

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