Identification and characterization of phosphodiesterases that specifically degrade 3′3′-cyclic GMP-AMP

被引:67
作者
Gao, Juyi [1 ,2 ,4 ]
Tao, Jianli [1 ,2 ,4 ]
Liang, Weili [5 ,6 ]
Zhao, Meng [5 ]
Du, Xiaoxia [1 ]
Cui, Shan [3 ]
Duan, Haifeng [3 ]
Kan, Biao [5 ,6 ]
Su, Xiaodong [1 ,3 ]
Jiang, Zhengfan [1 ,2 ,4 ]
机构
[1] Peking Univ, Sch Life Sci, State Key Lab Prot & Plant Gene Res, Beijing 100871, Peoples R China
[2] Peking Univ, Sch Life Sci, Minist Educ, Key Lab Cell Proliferat & Differentiat, Beijing 100871, Peoples R China
[3] Peking Univ, Sch Life Sci, Biodynam Opt Imaging Ctr BIOPIC, Beijing 100871, Peoples R China
[4] Peking Tsinghua Ctr Life Sci, Beijing, Peoples R China
[5] Chinese Ctr Dis Control & Prevent, Natl Inst Communicable Dis Control & Prevent, State Key Lab Infect Dis Prevent & Control, Beijing 102206, Peoples R China
[6] Collaborat Innovat Ctr Diag & Treatment Infect Di, Hangzhou 310003, Zhejiang, Peoples R China
基金
中国国家自然科学基金;
关键词
3 ' 3 '-cGAMP; V; cholera; phosphodiesterase; HD-GYP; CYCLIC-DI-GMP; EAL DOMAIN PROTEIN; VIBRIO-CHOLERAE; HD-GYP; 2ND-MESSENGER; VIRULENCE; GGDEF; REVEALS; ENZYME; SENSOR;
D O I
10.1038/cr.2015.40
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Cyclic dinucleotides act as intracellular second messengers, modulating a variety of cellular activities including innate immune activation. Although phosphodiesterases (PDEs) hydrolyzing c-di-GMP and c-di-AMP have been identified, no PDEs for cGAMPs have been reported. Here we identified the first three cGAMP-specific PDEs in V. cholerae (herein designated as V-cGAP1/2/3). V-cGAPs are HD-GYP domain-containing proteins and specifically break 3'3'-cGAMP, but not other forms of cGAMP. 3'3'-cGAMP is first linearized by all three V-cGAPs to produce 5'-pApG, which is further hydrolyzed into 5'-ApG by V-cGAP1. In this two-step reaction, V-cGAP1 functions as both a PDE and a 5'-nucleotidase. In vivo experiments demonstrated that V-cGAPs play non-redundant roles in cGAMP degradation. The high specificity of V-cGAPs on 3'3'-cGAMP suggests the existence of specific PDEs for other cGAMPs, including 2'3'-cGAMP in mammalian cells. The absolute requirement of the GYP motif for 3'3'-cGAMP degradation suggests that HD domain-containing PDEs in eukaryotes are probably unable to hydrolyze cGAMPs. The fact that all V-cGAPs attack 3'3'-cGAMP on one specific phosphodiester bond suggests that PDEs for other cGAMPs would utilize a similar strategy. These results will provide valuable information for identification and characterization of mammalian 2'3'-cGAMP-specific PDEs in future studies.
引用
收藏
页码:539 / 550
页数:12
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