Cyclic-GMP-AMP Is An Endogenous Second Messenger in Innate Immune Signaling by Cytosolic DNA
TLDR
Cytosolic DNA induces type I interferons and other cytokines that are important for antimicrobial defense but can also result in autoimmunity, and cGAMP functions as an endogenous second messenger in metazoans and triggers interferon production in response to cytosolicDNA.Abstract:
Cytosolic DNA induces type I interferons and other cytokines that are important for antimicrobial defense but can also result in autoimmunity. This DNA signaling pathway requires the adaptor protein STING and the transcription factor IRF3, but the mechanism of DNA sensing is unclear. We found that mammalian cytosolic extracts synthesized cyclic guanosine monophosphate–adenosine monophosphate (cyclic GMP-AMP, or cGAMP) in vitro from adenosine triphosphate and guanosine triphosphate in the presence of DNA but not RNA. DNA transfection or DNA virus infection of mammalian cells also triggered cGAMP production. cGAMP bound to STING, leading to the activation of IRF3 and induction of interferon-β. Thus, cGAMP functions as an endogenous second messenger in metazoans and triggers interferon production in response to cytosolic DNA.read more
Citations
More filters
Journal ArticleDOI
The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak - an update on the status.
Yan Rong Guo,Qing Dong Cao,Zhong Si Hong,Yuan Yang Tan,Shoudeng Chen,Hong Jun Jin,Kai Sen Tan,De Yun Wang,Yan Yan +8 more
TL;DR: The latest research progress of the epidemiology, pathogenesis, and clinical characteristics of COVID-19 are summarized, and the current treatment and scientific advancements to combat the epidemic novel coronavirus are discussed.
Journal ArticleDOI
Cyclic GMP-AMP Synthase is a Cytosolic DNA Sensor that Activates the Type-I Interferon Pathway
TL;DR: Results indicate that cGAS is a cytosolic DNA sensor that induces interferons by producing the second messenger cGAMP, which belongs to the nucleotidyltransferase family.
Journal ArticleDOI
Interferon-Stimulated Genes: A Complex Web of Host Defenses
TL;DR: This review begins by introducing interferon (IFN) and the JAK-STAT signaling pathway to highlight features that impact ISG production and describes ways in which ISGs both enhance innate pathogen-sensing capabilities and negatively regulate signaling through the Jak-STAT pathway.
Journal ArticleDOI
STING-Dependent Cytosolic DNA Sensing Promotes Radiation-Induced Type I Interferon-Dependent Antitumor Immunity in Immunogenic Tumors
Liufu Deng,Hua Liang,Meng Xu,Xuanming Yang,Byron Burnette,Ainhoa Arina,Xiao Dong Li,Helena J. Mauceri,Michael A. Beckett,Thomas E. Darga,Xiaona Huang,Thomas F. Gajewski,Zhijian J. Chen,Yang Xin Fu,Ralph R. Weichselbaum +14 more
TL;DR: Radiation-mediated antitumor immunity in immunogenic tumors requires a functional cytosolic DNA-sensing pathway and suggests that cGAMP treatment might provide a new strategy to improve radiotherapy.
Journal ArticleDOI
STING-Dependent Cytosolic DNA Sensing Mediates Innate Immune Recognition of Immunogenic Tumors
Seng Ryong Woo,Mercedes Beatriz Fuertes,Leticia Corrales,Stefani Spranger,Michael J. Furdyna,Michael Y. K. Leung,Ryan Duggan,Ying Wang,Glen N. Barber,Katherine A. Fitzgerald,Maria-Luisa Alegre,Thomas F. Gajewski +11 more
TL;DR: It is found that spontaneous CD8(+) T cell priming against tumors was defective in mice lacking stimulator of interferon genes complex (STING), but not other innate signaling pathways, suggesting involvement of a cytosolic DNA sensing pathway.
References
More filters
Journal ArticleDOI
Cyclic GMP-AMP Synthase is a Cytosolic DNA Sensor that Activates the Type-I Interferon Pathway
TL;DR: Results indicate that cGAS is a cytosolic DNA sensor that induces interferons by producing the second messenger cGAMP, which belongs to the nucleotidyltransferase family.
Journal ArticleDOI
Identification and Characterization of MAVS, a Mitochondrial Antiviral Signaling Protein that Activates NF-κB and IRF3
TL;DR: The identification of a novel protein termed MAVS (mitochondrial antiviral signaling), which mediates the activation of NF-kappaB and IRF 3 in response to viral infection, and implicates a new role of mitochondria in innate immunity.
Journal ArticleDOI
STING is a direct innate immune sensor of cyclic di-GMP
Dara Burdette,Kathryn M. Monroe,Katia Sotelo-Troha,Jeffrey S. Iwig,Barbara Eckert,Mamoru Hyodo,Yoshihiro Hayakawa,Russell E. Vance +7 more
TL;DR: It is demonstrated that STING binds directly to radiolabelled cyclic diguanylate monophosphate (c-di-GMP), and it is shown that unlabelledcyclic dinucleotides, but not other nucleotides or nucleic acids, compete with c-di -GMP for binding to STING.
Journal ArticleDOI
RNA Polymerase III Detects Cytosolic DNA and Induces Type-I Interferons Through the RIG-I Pathway
TL;DR: It is shown that the cytosolic poly(dA-dT) DNA is converted into 5'-ppp RNA to induce IFN-beta through the RIG-I pathway, suggesting that RNA Pol-III is a cytosol DNA sensor involved in innate immune responses.
Journal ArticleDOI
STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway.
Yasuo Tanaka,Zhijian J. Chen +1 more
TL;DR: STING is shown to stimulate phosphorylation of IRF3 by the kinase TBK1 (TANK-binding kinase 1) in an in vitro reconstitution system, suggesting that STING functions as a scaffold protein to specify and promote the phosphorylated of IRf3 by TBk1.
Related Papers (5)
Cyclic GMP-AMP Synthase is a Cytosolic DNA Sensor that Activates the Type-I Interferon Pathway
STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling.
Hiroki Ishikawa,Glen N. Barber +1 more