Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, 430071, China.
Department of Medical Parasitology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, 430071, China.
Cell Death Dis. 2024 Aug 26;15(8):618. doi: 10.1038/s41419-024-06886-1.
Acute liver failure (ALF) is characterized by the rapidly progressive deterioration of hepatic function, which, without effective medical intervention, results in high mortality and morbidity. Here, using proteomic and transcriptomic analyses in murine ALF models, we found that the expression of multiple splicing factors was downregulated in ALF. Notably, we found that KH-type splicing regulatory protein (KHSRP) has a protective effect in ALF. Knockdown of KHSRP resulted in dramatic splicing defects, such as intron retention, and led to the exacerbation of liver injury in ALF. Moreover, we demonstrated that KHSRP directly interacts with splicing factor 3b subunit 1 (SF3B1) and enhances the binding of SF3B1 to the intronic branch sites, thereby promoting pre-mRNA splicing. Using splicing inhibitors, we found that Khsrp protects against ALF by regulating pre-mRNA splicing in vivo. Overall, our findings demonstrate that KHSRP is an important splicing activator and promotes the expression of genes associated with ALF progression by interacting with SF3B1; thus, KHSRP could be a possible target for therapeutic intervention in ALF.
急性肝衰竭（ALF）的特征是肝功能迅速恶化，如果没有有效的医疗干预，会导致高死亡率和高发病率。在这里，我们使用小鼠 ALF 模型中的蛋白质组学和转录组学分析，发现 ALF 中多个剪接因子的表达下调。值得注意的是，我们发现 KH 型剪接调节蛋白（KHSRP）在 ALF 中具有保护作用。KHSRP 的敲低导致明显的剪接缺陷，如内含子保留，并导致 ALF 中肝损伤的加剧。此外，我们证明 KHSRP 直接与剪接因子 3b 亚基 1（SF3B1）相互作用，并增强 SF3B1 与内含子分支位点的结合，从而促进前体 mRNA 的剪接。使用剪接抑制剂，我们发现 Khsrp 通过调节体内前体 mRNA 的剪接来防止 ALF。总的来说，我们的研究结果表明 KHSRP 是一种重要的剪接激活剂，通过与 SF3B1 相互作用促进与 ALF 进展相关的基因表达；因此，KHSRP 可能是 ALF 治疗干预的一个潜在靶点。
