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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.
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页码:539 / 550
页数:12
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