Ubc9‐Mediated SUMOylation of RPL3, an Unappreciated Mechanism against Hepatocyte Senescence by Repressing the DHX9‐p16 Axis

Abstract Although Ubc9‐mediated SUMOylation are recognized to regulate the multiple aspects of hepatic biological processes, its impact on hepatic senescence and metabolic dysfunction‐associated steatotic liver disease (MASLD), however, is yet to be fully addressed. Herein noted an age‐dependent decrease of hepatic Ubc9 expression is first noted along with an escalated decrease of protein SUMOylation, which is coupled with enhanced senescent marker expressions both in humans and mice. Interestingly, Ubc9 is dispensable for liver development at the embryonic stage. However, Ubc9 deficiency in hepatocytes rendered mice with an exacerbated hepatic aging phenotype and more susceptible to fatty liver disease and steatohepatitis following the challenge of a methionine‐ and choline‐deficient (MCD)‐diet. Ii is further demonstrated that nuclear ribosomal protein L3 (RPL3) interacts with DExD/H‐box (DDX/DHX) helicases (DHX9), which then recruits RNA polymerase II to the p16 promoter to transcribe its expression, thereby exacerbating the hepatocyte aging process. However, Ubc9‐mediated SUMOylation prevents RPL3 nuclear translocation, by which it represses the expression of senescent markers such as p16 to attenuate the hepatic aging process. Together, the study highlights that Ubc9‐mediated SUMOylation of RPL3 could be an unappreciated mechanism against hepatic aging in clinical settings.