Pro-inflammation Associated with a Gain-of-Function Mutation (R284S) in the Innate Immune Sensor STING
Hiroyasu Konno,
Ivan K. Chinn,
Diana Hong,
Jordan S. Orange,
James R. Lupski,
Alejandra Mendoza,
Luis A. Pedroza,
Glen N. Barber
Affiliations
Hiroyasu Konno
Department of Cell Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Ivan K. Chinn
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
Diana Hong
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
Jordan S. Orange
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
James R. Lupski
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
Alejandra Mendoza
Colegio de Ciencias de la Salud-Hospital de los Valles, Universidad San Francisco de Quito, Quito, Ecuador
Luis A. Pedroza
Colegio de Ciencias de la Salud-Hospital de los Valles, Universidad San Francisco de Quito, Quito, Ecuador
Glen N. Barber
Department of Cell Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Corresponding author
Summary: 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. : 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. Keywords: STING, gain-of-function mutation, inflammatory disease, autoimmune disease, type I interferonopathy, ULK1 phosphorylation, AMPK inhibitor, STING inhibitor
