Identification and characterization of phosphodiesterases that specifically degrade 3'3'-cyclic GMP-AMP.
Identification and characterization of phosphodiesterases that specifically degrade 3'3'-cyclic GMP-AMP.
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特异性降解 3'3'-环 GMP-AMP 的磷酸二酯酶的鉴定和表征
作者：
环二核苷酸作为细胞内第二信使，调节多种细胞活动，包括先天免疫激活。虽然磷酸二酯酶（PDEs）水解c-二- gmp和c-二- amp已经被发现，但cGAMPs的PDEs尚未被报道。在这里，我们鉴定了霍乱弧菌中前三个cgamp特异性pde（这里指定为V-cGAP1/2/3）。V-cGAPs是一种含有HD-GYP结构域的蛋白，能够特异性地破坏3 ' 3 ' -cGAMP，而不是其他形式的cGAMP。3’3’-cGAMP首先被三种v - cgap线性化生成5’-pApG，再被v - cap1水解成5’-ApG。在这个两步反应中，V-cGAP1同时作为PDE和5 ' -核苷酸酶。体内实验表明，V-cGAPs在cGAMP降解中起非冗余作用。V-cGAPs对3 ' 3 ' -cGAMP的高特异性表明在哺乳动物细胞中存在对其他cgamp的特异性PDEs，包括2 ' 3 ' -cGAMP。GYP基序对3 ' 3 ' -cGAMP降解的绝对要求表明真核生物中含有HD结构域的PDEs可能无法水解cgamp。事实上，所有的V-cGAPs都会攻击一个特定磷酸二酯键上的3 ' 3 ' -cGAMP，这表明针对其他cgamp的pde也会使用类似的策略。这些结果将为今后哺乳动物2’3’- cgamp特异性PDEs的鉴定和表征提供有价值的信息。
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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影响因子：
3.6
作者：
Bellini D;Caly DL;McCarthy Y;Bumann M;An SQ;Dow JM;Ryan RP;Walsh MA
通讯作者：
Walsh MA
影响因子：
9.4
作者：
IWANAGA, M;YAMAMOTO, K
通讯作者：
YAMAMOTO, K
影响因子：
5.2
作者：
Ryan, Robert P.;Dow, J. Maxwell
通讯作者：
Dow, J. Maxwell
影响因子：
3.2
作者：
Lim, Bentley;Beyhan, Sinem;Yildiz, Fitnat H.
通讯作者：
Yildiz, Fitnat H.
影响因子：
4.8
作者：
Mehne, Felix M. P.;Gunka, Katrin;Stuelke, Joerg
通讯作者：
Stuelke, Joerg