ZCCHC3 is a co-sensor of cGAS for dsDNA recognition in innate immune response

Cyclic GMP-AMP synthase (cGAS) senses double-strand (ds) DNA in the cytosol and then catalyzes synthesis of the second messenger cGAMP, which activates the adaptor MITA/STING to initiate innate antiviral response. How cGAS activity is regulated remains enigmatic. Here, we identify ZCCHC3, a CCHC-typ...

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Published inNature communications Vol. 9; no. 1; pp. 3349 - 13
Main Authors Lian, Huan, Wei, Jin, Zang, Ru, Ye, Wen, Yang, Qing, Zhang, Xia-Nan, Chen, Yun-Da, Fu, Yu-Zhi, Hu, Ming-Ming, Lei, Cao-Qi, Luo, Wei-Wei, Li, Shu, Shu, Hong-Bing
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 22.08.2018
Nature Publishing Group
Nature Portfolio
Subjects
13/106
13/109
13/89
14/19
38/77
42/109
631/250/2499
631/250/262
631/326/596/2553
692/420/254
96
96/1
96/95
AMP
Animals
Binding
Chemical synthesis
Cyclic GMP
Cytosol
Deoxyribonucleic acid
DNA
DNA - genetics
DNA - metabolism
DNA viruses
Herpes simplex
Humanities and Social Sciences
Immune response
Immune system
Immunity, Innate - genetics
Immunity, Innate - physiology
Infections
Innate immunity
Mice
Mice, Knockout
multidisciplinary
Nucleotides, Cyclic - metabolism
Nucleotidyltransferases - genetics
Nucleotidyltransferases - metabolism
Proteins
Recognition
RNA Nucleotidyltransferases - genetics
RNA Nucleotidyltransferases - metabolism
Science
Signal Transduction - genetics
Signal Transduction - physiology
Viral infections
Viruses
Zinc
Zinc finger proteins
Online AccessGet full text

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Abstract Cyclic GMP-AMP synthase (cGAS) senses double-strand (ds) DNA in the cytosol and then catalyzes synthesis of the second messenger cGAMP, which activates the adaptor MITA/STING to initiate innate antiviral response. How cGAS activity is regulated remains enigmatic. Here, we identify ZCCHC3, a CCHC-type zinc-finger protein, as a positive regulator of cytosolic dsDNA- and DNA virus-triggered signaling. We show that ZCCHC3-deficiency inhibits dsDNA- and DNA virus-triggered induction of downstream effector genes, and that ZCCHC3-deficient mice are more susceptible to lethal herpes simplex virus type 1 or vaccinia virus infection. ZCCHC3 directly binds to dsDNA, enhances the binding of cGAS to dsDNA, and is important for cGAS activation following viral infection. Our results suggest that ZCCHC3 is a co-sensor for recognition of dsDNA by cGAS, which is important for efficient innate immune response to cytosolic dsDNA and DNA virus. cGAS is an important mediator of antiviral immune responses, but the regulation of its activity is unknown. Here, the authors identify a zinc finger protein, ZCCHC3, that enhances the binding of cGAS to dsDNA and is important for its activation following viral infection.
AbstractList Cyclic GMP-AMP synthase (cGAS) senses double-strand (ds) DNA in the cytosol and then catalyzes synthesis of the second messenger cGAMP, which activates the adaptor MITA/STING to initiate innate antiviral response. How cGAS activity is regulated remains enigmatic. Here, we identify ZCCHC3, a CCHC-type zinc-finger protein, as a positive regulator of cytosolic dsDNA- and DNA virus-triggered signaling. We show that ZCCHC3-deficiency inhibits dsDNA- and DNA virus-triggered induction of downstream effector genes, and that ZCCHC3-deficient mice are more susceptible to lethal herpes simplex virus type 1 or vaccinia virus infection. ZCCHC3 directly binds to dsDNA, enhances the binding of cGAS to dsDNA, and is important for cGAS activation following viral infection. Our results suggest that ZCCHC3 is a co-sensor for recognition of dsDNA by cGAS, which is important for efficient innate immune response to cytosolic dsDNA and DNA virus.cGAS is an important mediator of antiviral immune responses, but the regulation of its activity is unknown. Here, the authors identify a zinc finger protein, ZCCHC3, that enhances the binding of cGAS to dsDNA and is important for its activation following viral infection.
Cyclic GMP-AMP synthase (cGAS) senses double-strand (ds) DNA in the cytosol and then catalyzes synthesis of the second messenger cGAMP, which activates the adaptor MITA/STING to initiate innate antiviral response. How cGAS activity is regulated remains enigmatic. Here, we identify ZCCHC3, a CCHC-type zinc-finger protein, as a positive regulator of cytosolic dsDNA- and DNA virus-triggered signaling. We show that ZCCHC3-deficiency inhibits dsDNA- and DNA virus-triggered induction of downstream effector genes, and that ZCCHC3-deficient mice are more susceptible to lethal herpes simplex virus type 1 or vaccinia virus infection. ZCCHC3 directly binds to dsDNA, enhances the binding of cGAS to dsDNA, and is important for cGAS activation following viral infection. Our results suggest that ZCCHC3 is a co-sensor for recognition of dsDNA by cGAS, which is important for efficient innate immune response to cytosolic dsDNA and DNA virus.
Cyclic GMP-AMP synthase (cGAS) senses double-strand (ds) DNA in the cytosol and then catalyzes synthesis of the second messenger cGAMP, which activates the adaptor MITA/STING to initiate innate antiviral response. How cGAS activity is regulated remains enigmatic. Here, we identify ZCCHC3, a CCHC-type zinc-finger protein, as a positive regulator of cytosolic dsDNA- and DNA virus-triggered signaling. We show that ZCCHC3-deficiency inhibits dsDNA- and DNA virus-triggered induction of downstream effector genes, and that ZCCHC3-deficient mice are more susceptible to lethal herpes simplex virus type 1 or vaccinia virus infection. ZCCHC3 directly binds to dsDNA, enhances the binding of cGAS to dsDNA, and is important for cGAS activation following viral infection. Our results suggest that ZCCHC3 is a co-sensor for recognition of dsDNA by cGAS, which is important for efficient innate immune response to cytosolic dsDNA and DNA virus. cGAS is an important mediator of antiviral immune responses, but the regulation of its activity is unknown. Here, the authors identify a zinc finger protein, ZCCHC3, that enhances the binding of cGAS to dsDNA and is important for its activation following viral infection.
cGAS is an important mediator of antiviral immune responses, but the regulation of its activity is unknown. Here, the authors identify a zinc finger protein, ZCCHC3, that enhances the binding of cGAS to dsDNA and is important for its activation following viral infection.
Cyclic GMP-AMP synthase (cGAS) senses double-strand (ds) DNA in the cytosol and then catalyzes synthesis of the second messenger cGAMP, which activates the adaptor MITA/STING to initiate innate antiviral response. How cGAS activity is regulated remains enigmatic. Here, we identify ZCCHC3, a CCHC-type zinc-finger protein, as a positive regulator of cytosolic dsDNA- and DNA virus-triggered signaling. We show that ZCCHC3-deficiency inhibits dsDNA- and DNA virus-triggered induction of downstream effector genes, and that ZCCHC3-deficient mice are more susceptible to lethal herpes simplex virus type 1 or vaccinia virus infection. ZCCHC3 directly binds to dsDNA, enhances the binding of cGAS to dsDNA, and is important for cGAS activation following viral infection. Our results suggest that ZCCHC3 is a co-sensor for recognition of dsDNA by cGAS, which is important for efficient innate immune response to cytosolic dsDNA and DNA virus.Cyclic GMP-AMP synthase (cGAS) senses double-strand (ds) DNA in the cytosol and then catalyzes synthesis of the second messenger cGAMP, which activates the adaptor MITA/STING to initiate innate antiviral response. How cGAS activity is regulated remains enigmatic. Here, we identify ZCCHC3, a CCHC-type zinc-finger protein, as a positive regulator of cytosolic dsDNA- and DNA virus-triggered signaling. We show that ZCCHC3-deficiency inhibits dsDNA- and DNA virus-triggered induction of downstream effector genes, and that ZCCHC3-deficient mice are more susceptible to lethal herpes simplex virus type 1 or vaccinia virus infection. ZCCHC3 directly binds to dsDNA, enhances the binding of cGAS to dsDNA, and is important for cGAS activation following viral infection. Our results suggest that ZCCHC3 is a co-sensor for recognition of dsDNA by cGAS, which is important for efficient innate immune response to cytosolic dsDNA and DNA virus.
ArticleNumber 3349
Author Lian, Huan
Wei, Jin
Zhang, Xia-Nan
Shu, Hong-Bing
Hu, Ming-Ming
Zang, Ru
Li, Shu
Fu, Yu-Zhi
Lei, Cao-Qi
Luo, Wei-Wei
Chen, Yun-Da
Yang, Qing
Ye, Wen
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  organization: Medical Research Institute, School of Medicine, Wuhan University
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  organization: Medical Research Institute, School of Medicine, Wuhan University, College of Life Sciences Wuhan University
BackLink https://www.ncbi.nlm.nih.gov/pubmed/30135424$$D View this record in MEDLINE/PubMed
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2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
The Author(s) 2018. corrected publication 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
The Author(s) 2018, corrected publication 2021
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Snippet Cyclic GMP-AMP synthase (cGAS) senses double-strand (ds) DNA in the cytosol and then catalyzes synthesis of the second messenger cGAMP, which activates the...
cGAS is an important mediator of antiviral immune responses, but the regulation of its activity is unknown. Here, the authors identify a zinc finger protein,...
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AMP
Animals
Binding
Chemical synthesis
Cyclic GMP
Cytosol
Deoxyribonucleic acid
DNA
DNA - genetics
DNA - metabolism
DNA viruses
Herpes simplex
Humanities and Social Sciences
Immune response
Immune system
Immunity, Innate - genetics
Immunity, Innate - physiology
Infections
Innate immunity
Mice
Mice, Knockout
multidisciplinary
Nucleotides, Cyclic - metabolism
Nucleotidyltransferases - genetics
Nucleotidyltransferases - metabolism
Proteins
Recognition
RNA Nucleotidyltransferases - genetics
RNA Nucleotidyltransferases - metabolism
Science
Signal Transduction - genetics
Signal Transduction - physiology
Viral infections
Viruses
Zinc
Zinc finger proteins
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Title ZCCHC3 is a co-sensor of cGAS for dsDNA recognition in innate immune response
URI https://link.springer.com/article/10.1038/s41467-018-05559-w
https://www.ncbi.nlm.nih.gov/pubmed/30135424
https://www.proquest.com/docview/2091749319
https://www.proquest.com/docview/2572354104
https://www.proquest.com/docview/2092533909
https://pubmed.ncbi.nlm.nih.gov/PMC6105683
https://doaj.org/article/787e1f46425144ed98d0dc92723cdac6
Volume 9
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