School of Life Science and Technology, China Pharmaceutical University, Nanjing, China.
Cell Death Dis. 2024 Aug 20;15(8):602. doi: 10.1038/s41419-024-06997-9.
Sulfenylation is a reversible oxidative posttranslational modification (PTM) of proteins on cysteine residues. Despite the dissection of various biological functions of cysteine sulfenylation, its roles in hepatic fibrosis remain elusive. Here, we report that EphB2, a receptor tyrosine kinase previously implicated in liver fibrosis, is regulated by cysteine sulfenylation during the fibrotic progression of liver. Specifically, EphB2 is sulfenylated at the residues of Cys636 and Cys862 in activated hepatic stellate cells (HSCs), leading to the elevation of tyrosine kinase activity and protein stability of EphB2 and stronger interactions with focal adhesion kinase for the activation of downstream mitogen-activated protein kinase signaling. The inhibitions of both EphB2 kinase activity and cysteine sulfenylation by idebenone (IDE), a marketed drug with potent antioxidant activity, can markedly suppress the activation of HSCs and ameliorate hepatic injury in two well-recognized mouse models of liver fibrosis. Collectively, this study reveals cysteine sulfenylation as a new type of PTM for EphB2 and sheds a light on the therapeutic potential of IDE for the treatment of liver fibrosis.
磺化作用是蛋白质半胱氨酸残基上的一种可逆氧化翻译后修饰（PTM）。尽管对半胱氨酸磺化作用的各种生物学功能进行了剖析，但它在肝纤维化中的作用仍不清楚。在这里，我们报告称，EphB2 是一种先前被认为与肝纤维化有关的受体酪氨酸激酶，在肝纤维化进展过程中受半胱氨酸磺化作用调节。具体来说，EphB2 在活化的肝星状细胞（HSCs）中半胱氨酸残基 Cys636 和 Cys862 上发生磺化，导致 EphB2 的酪氨酸激酶活性和蛋白稳定性升高，与粘着斑激酶的相互作用增强，从而激活下游丝裂原活化蛋白激酶信号。伊地苯醌（IDE）是一种具有强大抗氧化活性的市售药物，可抑制 EphB2 激酶活性和半胱氨酸磺化作用，可显著抑制 HSCs 的活化，并改善两种公认的肝纤维化小鼠模型中的肝损伤。总之，这项研究揭示了半胱氨酸磺化作用是 EphB2 的一种新型 PTM，并为 IDE 治疗肝纤维化的治疗潜力提供了线索。
