title: Single amino acid change in STING leads to constitutive active signaling.
abstract: The production of cytokines by the immune system in response to cytosolic DNA plays an important role in host defense, autoimmune disease, and cancer immunogenicity. Recently a cytosolic DNA signaling pathway that is dependent on the endoplasmic reticulum adaptor and cyclic dinucleotide sensor protein STING has been identified. Association of cytosolic DNA with cyclic-GMP-AMP synthase (cGAS) activates its enzymatic activity to synthesize the cyclic dinucleotide second messenger cGAMP from GTP and ATP. Direct detection of cGAMP by STING triggers the activation of IRF3 and NF-kB, and the production of type I interferons and proinflammatory cytokines. The mechanism of how STING is able to mediate downstream signaling remains incompletely understood although it has been shown that dimerization is a prerequisite. Here, we identify a single amino acid change in STING that confers constitutive active signaling. This mutation appears to both enhance ability of STING to both dimerize and associate with its downstream target TBK1.
authors: Laboratory of Molecular Signaling, Division of Oral Biology & Medicine, UCLA School of Dentistry, Los Angeles, CA, United States of America.
authors: Eric D
authors: ED
authors: Tang
authors: Laboratory of Molecular Signaling, Division of Oral Biology & Medicine, UCLA School of Dentistry, Los Angeles, CA, United States of America.
authors: Cun-Yu
authors: CY
authors: Wang
mesh_terms: D019943:Amino Acid Substitution; D006152:Cyclic GMP / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D020125:Mutation, Missense; D016328:NF-kappa B / Q000378:metabolism; D009713:Nucleotidyltransferases / Q000378:metabolism; D055503:Protein Multimerization; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D000099197:STING Protein; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D006152:Cyclic GMP; D004247:DNA; D050838:Interferon Regulatory Factor-3; D008565:Membrane Proteins; D016328:NF-kappa B; D009713:Nucleotidyltransferases; D017346:Protein Serine-Threonine Kinases; C494232:IRF3 protein, human; C532857:STING1 protein, human; D000099197:STING Protein; C403191:TBK1 protein, human; C578390:cGAS protein, human; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase