Characterization of a toxin-antitoxin system in Mycobacterium tuberculosis suggests neutralization by phosphorylation as the antitoxicity mechanism
Characterization of a toxin-antitoxin system in Mycobacterium tuberculosis suggests neutralization by phosphorylation as the antitoxicity mechanism
复制标题
结核分枝杆菌毒素-抗毒素系统的表征表明通过磷酸化中和作为抗毒性机制
DOI：
10.1038/s42003-020-0941-1
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发表时间：
2020-05-07
影响因子：
5.9
通讯作者：
Cui, Sheng
中科院分区：
文献类型：
--
作者：
Yu, Xia;Gao, Xiaopan;Cui, Sheng
结核分枝杆菌（Mtb）编码异常大量的毒素-抗毒素（TA）系统，支持TA系统参与发病机制的假设。我们的特点是推定的结核分枝杆菌Rv 1044-Rv 1045 TA位点的结构和功能，表明它构成了一个真正的TA系统，但采用了以前未观察到的抗毒性机制，涉及磷酸化的毒素。Rv 1045编码作为毒素发挥作用的鸟苷酰转移酶TglT，而Rv 1044编码新的非典型丝氨酸蛋白激酶TakA，其特异性磷酸化残基S78处的同源毒素，从而中和其毒性。与以前的预测相反，我们发现Rv 1044-Rv 1045不属于IV型TA家族，因为TglT和TakA作为底物和激酶相互作用，这表明TA系统的不寻常类型。蛋白质同源性分析表明，其他COG 5340-DUF 1814蛋白对，两个高度相关，但在原核生物中广泛存在的蛋白质家族，可能会分享这种不寻常的抗毒性机制。
Mycobacterium tuberculosis (Mtb) encodes an exceptionally large number of toxin-antitoxin (TA) systems, supporting the hypothesis that TA systems are involved in pathogenesis. We characterized the putative Mtb Rv1044-Rv1045 TA locus structurally and functionally, demonstrating that it constitutes a bona fide TA system but adopts a previously unobserved antitoxicity mechanism involving phosphorylation of the toxin. While Rv1045 encodes the guanylyltransferase TglT functioning as a toxin, Rv1044 encodes the novel atypical serine protein kinase TakA, which specifically phosphorylates the cognate toxin at residue S78, thereby neutralizing its toxicity. In contrast to previous predictions, we found that Rv1044-Rv1045 does not belong to the type IV TA family because TglT and TakA interact with each other as substrate and kinase, suggesting an unusual type of TA system. Protein homology analysis suggests that other COG5340-DUF1814 protein pairs, two highly associated but uncharacterized protein families widespread in prokaryotes, might share this unusual antitoxicity mechanism.