Mycoplasma glycine cleavage system key subunit GcvH is an apoptosis inhibitor targeting host endoplasmic reticulum

文献类型： 外文期刊

第一作者： Pan, Qiao

作者： Pan, Qiao;Zhang, Yujuan;Liu, Tong;Xu, Qingyuan;Wu, Qi;Xin, Jiuqing;Xu, Qingyuan

作者机构：

期刊名称：PLOS PATHOGENS （ 影响因子：6.7； 五年影响因子：6.7 ）

ISSN： 1553-7366

年卷期： 2024 年 20 卷 5 期

页码：

收录情况： SCI

摘要： Mycoplasmas are minimal but notorious bacteria that infect humans and animals. These genome-reduced organisms have evolved strategies to overcome host apoptotic defense and establish persistent infection. Here, using Mycoplasma bovis as a model, we demonstrate that mycoplasma glycine cleavage system (GCS) H protein (GcvH) targets the endoplasmic reticulum (ER) to hijack host apoptosis facilitating bacterial infection. Mechanically, GcvH interacts with the ER-resident kinase Brsk2 and stabilizes it by blocking its autophagic degradation. Brsk2 subsequently disturbs unfolded protein response (UPR) signaling, thereby inhibiting the key apoptotic molecule CHOP expression and ER-mediated intrinsic apoptotic pathway. CHOP mediates a cross-talk between ER- and mitochondria-mediated intrinsic apoptosis. The GcvH N-terminal amino acid 31-35 region is necessary for GcvH interaction with Brsk2, as well as for GcvH to exert anti-apoptotic and potentially pro-infective functions. Notably, targeting Brsk2 to dampen apoptosis may be a conserved strategy for GCS-containing mycoplasmas. Our study reveals a novel role for the conserved metabolic route protein GcvH in Mycoplasma species. It also sheds light on how genome-reduced bacteria exploit a limited number of genomic proteins to resist host cell apoptosis thereby facilitating pathogenesis. Mycoplasma-related debilitating and chronic diseases have long troubled human and animal health. A better understanding of mycoplasma pathogenesis helps to develop effective control strategies. Some mycoplasmas have been reported to delay or inhibit host apoptosis, which could be an important pathogenic mechanism for Mycoplasma organisms. In the present study, we propose the first molecular mechanism model describing how GCS-containing mycoplasmas counteract host cell apoptosis. We found that the mycoplasma glycine cleavage system subunit H (GcvH) doubles as an apoptosis inhibitor. It binds to and stabilizes the ER-resident kinase Brsk2, which subsequently disturbs unfolded protein response (UPR) signaling. This disturbance leads to the inhibition of the key apoptotic molecule CHOP expression and ER-mediated intrinsic apoptotic pathway. CHOP further transduces this anti-apoptosis signal to mitochondria. Notably, GcvH N-terminal amino acid 31-35 region was necessary for its interaction with Brsk2, as well as for GcvH anti-apoptotic and potentially pro-infective activity. Our study unveils strategies by which genome-reduced bacteria exploit a limited number of genomic proteins to resist host cell apoptosis thereby enhancing pathogenesis.

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