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

## TL;DR

The paper shows that Ubc9-mediated SUMOylation of RPL3 prevents liver aging by blocking p16 expression, offering a new therapeutic target for liver diseases.

## Contribution

The study identifies a novel mechanism involving Ubc9-mediated SUMOylation of RPL3 to repress hepatocyte senescence via the DHX9-p16 axis.

## Key findings

- Reduced Ubc9 expression in aging livers correlates with increased hepatocyte senescence and MASLD susceptibility.
- Ubc9-mediated SUMOylation of RPL3 prevents its nuclear translocation and represses p16 expression.
- Targeting Ubc9 could be a promising therapeutic strategy for liver aging and related diseases.

## 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.

Liver aging is characterized by a decline in the expression of the SUMO‐conjugating enzyme Ubc9, resulting in reduced SUMOylation levels in hepatocytes, particularly in the case of ribosomal protein RPL3. Disruption of RPL3 SUMOylation increases its nuclear translocation. Interestingly, ribosome‐free RPL3 facilitates the recruitment of helicase DHX9 to the promoter region of p16 within the nuclear, subsequently engaging RNA Pol II and enhancing the expression of the aging trigger factor p16. Consequently, targeting Ubc9 holds promise as a therapeutic strategy for treating liver aging in clinical settings.