Cyclic GMP-AMP synthase is activated by double-stranded DNA-induced oligomerization

Immunity
Xin LiPingwei Li

Abstract

Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor mediating innate antimicrobial immunity. It catalyzes the synthesis of a noncanonical cyclic dinucleotide, 2',5' cGAMP, that binds to STING and mediates the activation of TBK1 and IRF-3. Activated IRF-3 translocates to the nucleus and initiates the transcription of the IFN-β gene. The structure of mouse cGAS bound to an 18 bp dsDNA revealed that cGAS interacts with dsDNA through two binding sites, forming a 2:2 complex. Enzyme assays and IFN-β reporter assays of cGAS mutants demonstrated that interactions at both DNA binding sites are essential for cGAS activation. Mutagenesis and DNA binding studies showed that the two sites bind dsDNA cooperatively and that site B plays a critical role in DNA binding. The structure of mouse cGAS bound to dsDNA and 2',5' cGAMP provided insight into the catalytic mechanism of cGAS. These results demonstrated that cGAS is activated by dsDNA-induced oligomerization.

References

Feb 2, 1999·Journal of Molecular Biology·L Lo ConteJ Janin
Dec 29, 2000·Nature·H HemmiS Akira
Apr 15, 2003·Nature Immunology·Katherine A FitzgeraldTom Maniatis
Jan 18, 2006·Immunity·Daniel B Stetson, Ruslan Medzhitov
May 13, 2009·Proceedings of the National Academy of Sciences of the United States of America·Wenxiang SunZhengfan Jiang
Jan 26, 2010·Nature Reviews. Immunology·Veit Hornung, Eicke Latz
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Paul D AdamsPeter H Zwart
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·Martyn D WinnKeith S Wilson
Sep 3, 2011·Immunological Reviews·Hiroki KatoTakashi Fujita
Sep 22, 2011·Nature Immunology·Glen N Barber
Sep 24, 2011·Trends in Immunology·Sinead E KeatingAndrew G Bowie
Sep 29, 2011·Nature·Dara L BurdetteRussell E Vance
Mar 8, 2012·Science Signaling·Yasuo Tanaka, Zhijian J Chen
Jun 26, 2012·Nature Structural & Molecular Biology·Yi-He HuangXiao-Dong Su
Jun 26, 2012·Nature Structural & Molecular Biology·Guijun ShangLichuan Gu
Dec 15, 2012·Nature Immunology·Dara L Burdette, Russell E Vance
Jan 16, 2013·Proceedings of the National Academy of Sciences of the United States of America·Jesse DonovanAlexei Korennykh
Jun 1, 2013·Nature·Filiz CivrilKarl-Peter Hopfner
Sep 3, 2013·Cell·Olga Danilchanka, John J Mekalanos
Jan 1, 1997·Methods in Enzymology·Zbyszek Otwinowski, Wladek Minor

❮ Previous
Next ❯

Citations

Mar 25, 2014·Annual Review of Immunology·Jiaxi Wu, Zhijian J Chen
Sep 17, 2014·Seminars in Immunopathology·Olivier DemariaMichel Gilliet
Feb 18, 2016·Current HIV/AIDS Reports·Nadia R Roan, Martin R Jakobsen
Jul 8, 2015·Proceedings of the National Academy of Sciences of the United States of America·Heping ShiChuo Chen
Sep 16, 2015·Proceedings of the National Academy of Sciences of the United States of America·Daxing GaoZhijian J Chen
May 2, 2014·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Jonathan MaelfaitJan Rehwinkel
Sep 19, 2015·Nature Immunology·Jessica J Chiang, Michaela U Gack
Sep 1, 2015·Cell Host & Microbe·Jian-jun WuFanxiu Zhu
Aug 19, 2014·Cell·Philip J KranzuschJennifer A Doudna
Apr 29, 2014·Molecular Cell·Xin CaiZhijian J Chen
Dec 18, 2013·Immunity·Philip J Kranzusch, Russell E Vance
Jul 11, 2014·Cytokine & Growth Factor Reviews·Chang ShuPingwei Li
Jan 27, 2015·Annual Review of Immunology·Qian YinHao Wu
Mar 11, 2015·Genome Biology and Evolution·Alessandra MozziManuela Sironi
Jul 2, 2014·Nucleic Acids Research·Xiaomei WuZhen-Ming Pei
Sep 25, 2014·Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research·Susan Carpenter, Katherine A Fitzgerald
Apr 21, 2016·Immunity·Axel RoersVeit Hornung
May 8, 2016·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Andrea Ablasser, Muhammed F Gulen
Jun 16, 2016·Proceedings of the National Academy of Sciences of the United States of America·Baoyu ZhaoPingwei Li
Jul 1, 2016·Molecular Therapy : the Journal of the American Society of Gene Therapy·Xiaoou JiangVolker Patzel
Jul 28, 2016·Nature Reviews. Immunology·Martin Schlee, Gunther Hartmann
Sep 11, 2016·Mechanisms of Ageing and Development·Stephan GasserFlorence S G Cheung
Nov 1, 2016·Protein & Cell·Pengyan XiaZusen Fan
Dec 3, 2016·The Journal of General Virology·Jing HeDeyin Guo
Feb 1, 2017·Proceedings of the National Academy of Sciences of the United States of America·Hua WangZhijian J Chen
Nov 20, 2016·Arthritis & Rheumatology·Jie AnKeith B Elkon
Mar 24, 2017·International Reviews of Immunology·Daisuke OriTaro Kawai
Apr 13, 2017·Annual Review of Biochemistry·Kazuki KatoOsamu Nureki
Mar 22, 2018·Future Medicinal Chemistry·Modi WangHerman O Sintim
Apr 2, 2017·The Journal of Immunology : Official Journal of the American Association of Immunologists·Jianli TaoXiao-Dong Su
Sep 25, 2017·Protein Science : a Publication of the Protein Society·Justin HallAnn E Aulabaugh
Mar 31, 2015·The Journal of Immunology : Official Journal of the American Association of Immunologists·Jie AnKeith B Elkon

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antivirals (ASM)

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.

Antivirals

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.