Single amino acid change in STING leads to constitutive active signaling.

PloS One
Eric D Tang, Cun-Yu Wang

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.

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Citations

Feb 2, 2016·Veterinary Immunology and Immunopathology·Xiaozhan ZhangShoujun Li
Jan 16, 2016·The Journal of Allergy and Clinical Immunology·Bodo GrimbacherHans-Hartmut Peter
Jan 15, 2017·The Journal of Allergy and Clinical Immunology·Isabelle MelkiYanick J Crow
Apr 27, 2017·Annals of Oncology : Official Journal of the European Society for Medical Oncology·T ShekarianA Marabelle
Apr 17, 2019·Journal of Leukocyte Biology·Vijay Kumar
May 8, 2018·Genes and Immunity·Seema Patel, Lei Jin
Jun 10, 2017·Journal of Inflammation·Yang LiEndre Kiss-Toth
Feb 19, 2021·Proceedings of the National Academy of Sciences of the United States of America·Alexandra M MooreTimothy R Donahue
Mar 8, 2021·Molecular Therapy : the Journal of the American Society of Gene Therapy·Sze-Wah TseEric Huang
Sep 5, 2021·Proceedings of the National Academy of Sciences of the United States of America·Keke LiangCaius G Radu

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Methods Mentioned

BETA
transfections
PCR
coimmunoprecipitation
enzyme-linked immunosorbent assays
transfection
flow
Flow Cytometry
pull down

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