Degradation of splicing factor SRSF3 contributes to progressive liver disease

Area of Science:

• Hepatology
• Molecular Biology
• RNA Splicing

Background:

• Serine rich splicing factor 3 (SRSF3) is crucial for liver function.
• Loss of SRSF3 is linked to liver damage, regeneration, and hepatocellular carcinoma.
• SRSF3 levels are reduced in human non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and cirrhosis.

Purpose of the Study:

• To investigate the role of SRSF3 in metabolic liver disease.
• To elucidate the mechanism of SRSF3 regulation in the liver.
• To determine if targeting SRSF3 degradation can prevent liver disease progression.

Main Methods:

• Analysis of human liver samples and mouse models of NAFLD/NASH.
• Investigating SRSF3 expression and RNA splicing alterations.
• Studying the effect of palmitic acid-induced oxidative stress on SRSF3.
• Utilizing site-directed mutagenesis (SRSF3-K11R) to block neddylation and degradation.
• Evaluating the therapeutic potential of preventing SRSF3 degradation in vivo.

Main Results:

• SRSF3 expression and RNA splicing are dysregulated in NAFLD/NASH.
• Palmitic acid induces SRSF3 degradation via neddylation and proteasome pathway.
• Mutation at lysine 11 (SRSF3-K11R) prevents SRSF3 degradation and splicing alterations.
• In vivo prevention of SRSF3 degradation partially protected mice from steatosis, fibrosis, and inflammation.

Conclusions:

• SRSF3 degradation, regulated by neddylation, is a key mechanism disrupted in early metabolic liver disease.
• This disruption contributes to the progression of NAFLD to NASH, cirrhosis, and hepatocellular carcinoma.
• Targeting SRSF3 neddylation and degradation may offer a therapeutic strategy for liver disease.