Tetrahydrobiopterin metabolism attenuates ROS generation and radiosensitivity through LDHA S-nitrosylation: novel insight into radiogenic lung injury

四氢生物蝶呤 S-亚硝基化 生物蝶呤 GTP环水解酶I 化学 一氧化氮 活性氧 氧化应激 细胞生物学 亚硝化 生物化学 生物 一氧化氮合酶 半胱氨酸 有机化学
作者
Yang Feng,Yahui Feng,Liming Gu,Wei Mo,Xi Wang,Bin Song,Min Hee Hong,Fenghao Geng,Pei Huang,Hongying Yang,Wei Zhu,Yang Jiao,Qi Zhang,Wei‐Qun Ding,Jianping Cao,Shuyu Zhang
出处
期刊:Experimental and Molecular Medicine [Springer Nature]
卷期号:56 (5): 1107-1122 被引量:12
标识
DOI:10.1038/s12276-024-01208-z
摘要

Abstract Genotoxic therapy triggers reactive oxygen species (ROS) production and oxidative tissue injury. S-nitrosylation is a selective and reversible posttranslational modification of protein thiols by nitric oxide (NO), and 5,6,7,8-tetrahydrobiopterin (BH4) is an essential cofactor for NO synthesis. However, the mechanism by which BH4 affects protein S-nitrosylation and ROS generation has not been determined. Here, we showed that ionizing radiation disrupted the structural integrity of BH4 and downregulated GTP cyclohydrolase I (GCH1), which is the rate-limiting enzyme in BH4 biosynthesis, resulting in deficiency in overall protein S-nitrosylation. GCH1-mediated BH4 synthesis significantly reduced radiation-induced ROS production and fueled the global protein S-nitrosylation that was disrupted by radiation. Likewise, GCH1 overexpression or the administration of exogenous BH4 protected against radiation-induced oxidative injury in vitro and in vivo. Conditional pulmonary Gch1 knockout in mice ( Gch1 fl/fl ; Sftpa1-Cre +/− mice) aggravated lung injury following irradiation, whereas Gch1 knock-in mice ( Gch1 lsl/lsl ; Sftpa1-Cre +/− mice) exhibited attenuated radiation-induced pulmonary toxicity. Mechanistically, lactate dehydrogenase (LDHA) mediated ROS generation downstream of the BH4/NO axis, as determined by iodoacetyl tandem mass tag (iodoTMT)-based protein quantification. Notably, S-nitrosylation of LDHA at Cys163 and Cys293 was regulated by BH4 availability and could restrict ROS generation. The loss of S-nitrosylation in LDHA after irradiation increased radiosensitivity. Overall, the results of the present study showed that GCH1-mediated BH4 biosynthesis played a key role in the ROS cascade and radiosensitivity through LDHA S-nitrosylation, identifying novel therapeutic strategies for the treatment of radiation-induced lung injury.
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