High-throughput mRNA-sequence of KSRP knock down cells in HL7702 CELLS

RNA splicing is an essential step for expression of genes commonly altered in multiple liver diseases. However, how the spliceosomal components participate in the pathogenesis of acute liver failure (ALF) remains poorly defined. Here, we report that KH-type splicing regulatory protein (KSRP) which is downregulated in ALF, regulates RNA splicing in the liver through interacting with the Splicing factor 3b subunit 1 (SF3B1). Overexpression of KSRP resulted in marked amelioration of hepatic injury in vivo. Transcriptomic analysis reveals that KSRP depletion led to severe splicing defects in genes with significant intron retention. Such defects cause substantial loss of proliferation and apoptosis related genes such as EGFR, which further exaggerated liver injury. KSRP promotes RNA splicing of splicing related genes, including SF3B1, PHF5A, and SF3B4, indicating the existence of a positive feedback loop that regulates RNA splicing. Mechanistically, KSRP directly interacts with SF3B1 and enhances binding of SF3B1 to the branch sites located upstream of the exon. Overall, our findings demonstrate a novel mechanism by which KSPR protects against acute liver injury by promoting RNA splicing through interacting with the SF3B complex.