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

被引：120
作者：
Lian, Huan [1 ]
Wei, Jin [1 ]
Zang, Ru [1 ]
Ye, Wen [1 ]
Yang, Qing [1 ]
Zhang, Xia-Nan [1 ,2 ]
Chen, Yun-Da [1 ,2 ]
Fu, Yu-Zhi [3 ]
Hu, Ming-Ming [1 ]
Lei, Cao-Qi [1 ,2 ]
Luo, Wei-Wei [3 ]
Li, Shu [1 ]
Shu, Hong-Bing [1 ,2 ]
机构：
[1] Wuhan Univ, Med Res Inst, Sch Med, Wuhan 430071, Hubei, Peoples R China
[2] Wuhan Univ, Coll Life Sci, Wuhan 430072, Hubei, Peoples R China
[3] Chinese Acad Sci, Wuhan Inst Virol, Wuhan 430071, Hubei, Peoples R China
来源：
NATURE COMMUNICATIONS | 2018年 / 9卷
基金：
中国国家自然科学基金;
关键词：
CYCLIC GMP-AMP; CYTOSOLIC DNA SENSOR; INTRACELLULAR DNA; DENDRITIC CELLS; MYCOBACTERIUM-TUBERCULOSIS; ANTIVIRAL RESPONSE; I INTERFERONS; ADAPTER; SYNTHASE; 2ND-MESSENGER;
D O I：
10.1038/s41467-018-05559-w
中图分类号：
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号：
07 ; 0710 ; 09 ;
摘要：
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.
引用
收藏
页数：13
相关论文
共 46 条
[1]   STING Recognition of Cytoplasmic DNA Instigates Cellular Defense [J].
Abe, Takayuki ;
Harashima, Ai ;
Xia, Tianli ;
Konno, Hiroyasu ;
Konno, Keiko ;
Morales, Alejo ;
Ahn, Jeonghyun ;
Gutman, Delia ;
Barber, Glen N. .
MOLECULAR CELL, 2013, 50 (01) :5-15
[2]   cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING [J].
Ablasser, Andrea ;
Goldeck, Marion ;
Cavlar, Taner ;
Deimling, Tobias ;
Witte, Gregor ;
Roehl, Ingo ;
Hopfner, Karl-Peter ;
Ludwig, Janos ;
Hornung, Veit .
NATURE, 2013, 498 (7454) :380-+
[3]   RIG-I-dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III-transcribed RNA intermediate [J].
Ablasser, Andrea ;
Bauernfeind, Franz ;
Hartmann, Gunther ;
Latz, Eicke ;
Fitzgerald, Katherine A. ;
Hornung, Veit .
NATURE IMMUNOLOGY, 2009, 10 (10) :1065-U40
[4]   Pathogen recognition and innate immunity [J].
Akira, S ;
Uematsu, S ;
Takeuchi, O .
CELL, 2006, 124 (04) :783-801
[5]   cGAS senses long and HMGB/TFAM-bound U-turn DNA by forming protein-DNA ladders [J].
Andreeva, Liudmila ;
Hiller, Bjoern ;
Kostrewa, Dirk ;
Laessig, Charlotte ;
Mann, Carina C. de Oliveira ;
Drexler, David Jan ;
Maiser, Andreas ;
Gaidt, Moritz ;
Leonhardt, Heinrich ;
Hornung, Veit ;
Hopfner, Karl-Peter .
NATURE, 2017, 549 (7672) :394-+
[6]   STING-dependent signaling [J].
Barber, Glen N. .
NATURE IMMUNOLOGY, 2011, 12 (10) :929-930
[7]   The STING in the Tail for Cytosolic DNA-Dependent Activation of IRF3 [J].
Bowie, Andrew .
SCIENCE SIGNALING, 2012, 5 (214)
[8]   Post-transcriptional regulation of gene expression in innate immunity [J].
Carpenter, Susan ;
Ricci, Emiliano P. ;
Mercier, Blandine C. ;
Moore, Melissa J. ;
Fitzgerald, Katherine A. .
NATURE REVIEWS IMMUNOLOGY, 2014, 14 (06) :361-376
[9]   RNA Polymerase III Detects Cytosolic DNA and Induces Type I Interferons through the RIG-I Pathway [J].
Chiu, Yu-Hsin ;
MacMillan, John B. ;
Chen, Zhijian J. .
CELL, 2009, 138 (03) :576-591
[10]   Structural mechanism of cytosolic DNA sensing by cGAS [J].
Civril, Filiz ;
Deimling, Tobias ;
Mann, Carina C. de Oliveira ;
Ablasser, Andrea ;
Moldt, Manuela ;
Witte, Gregor ;
Hornung, Veit ;
Hopfner, Karl-Peter .
NATURE, 2013, 498 (7454) :332-+
12345