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KHSRP ameliorates acute liver failure by regulating pre-mRNA splicing through its interaction with SF3B1.
- Source :
-
Cell death & disease [Cell Death Dis] 2024 Aug 26; Vol. 15 (8), pp. 618. Date of Electronic Publication: 2024 Aug 26. - Publication Year :
- 2024
-
Abstract
- 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.<br /> (© 2024. The Author(s).)
- Subjects :
- Animals
Mice
Humans
Mice, Inbred C57BL
Male
Phosphoproteins metabolism
Phosphoproteins genetics
Disease Models, Animal
Protein Binding
Trans-Activators
RNA Splicing Factors metabolism
RNA Splicing Factors genetics
RNA-Binding Proteins metabolism
RNA-Binding Proteins genetics
RNA Splicing genetics
Liver Failure, Acute metabolism
Liver Failure, Acute genetics
RNA Precursors metabolism
RNA Precursors genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2041-4889
- Volume :
- 15
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Cell death & disease
- Publication Type :
- Academic Journal
- Accession number :
- 39187547
- Full Text :
- https://doi.org/10.1038/s41419-024-06886-1