UFMylation safeguards human hepatocyte differentiation and liver homeostasis by regulating ribosome dissociation

Shuchun Yang; Li Wang; Ran Gao; Yanchang Li; Duo Zhang; Chenxi Wang; Guang Liu; Jie Na; Ping Xu; Xiaoyue Wang; Yuyan Jia; Yue Huang

doi:10.1016/j.celrep.2025.115686

UFMylation safeguards human hepatocyte differentiation and liver homeostasis by regulating ribosome dissociation

Cell Rep. 2025 May 27;44(5):115686. doi: 10.1016/j.celrep.2025.115686. Epub 2025 May 9.

Authors

Shuchun Yang¹, Li Wang¹, Ran Gao², Yanchang Li³, Duo Zhang¹, Chenxi Wang¹, Guang Liu¹, Jie Na⁴, Ping Xu³, Xiaoyue Wang², Yuyan Jia⁵, Yue Huang⁶

Affiliations

¹ State Key Laboratory of Common Mechanism Research for Major Disease, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China; Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
² State Key Laboratory of Common Mechanism Research for Major Disease, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
³ State Key Laboratory of Medical Proteomics, Beijng Proteome Research Center, National Center for Protein Sciences (Beijing), Research Unit of Proteomics & Research and Development of New Drugs of Chinese Academy of Medical Sciences, Institute of Lifeomics, Beijing 102206, China.
⁴ Center for Stem Cell Biology and Regenerative Medicine, School of Medicine, Tsinghua University, Beijing, China.
⁵ State Key Laboratory of Common Mechanism Research for Major Disease, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China; Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China. Electronic address: jiayuyan@ibms.pumc.edu.cn.
⁶ State Key Laboratory of Common Mechanism Research for Major Disease, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China; Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China. Electronic address: huangyue@pumc.edu.cn.

PMID: 40347470
DOI: 10.1016/j.celrep.2025.115686

Abstract

Ribosomal UFMylation contributes to ribosome heterogeneity and is associated with ribosome-associated quality control at the endoplasmic reticulum. However, the specific pathophysiological functions of ribosomal UFMylation remain unknown. In this study, we systematically demonstrate the significance of UFMylation in the differentiation and maturation of hepatocytes using human embryonic stem cell-derived hepatocyte-like cells and liver bud organoids as experimental platforms. We also develop a strategy to identify UFMylated substrates and confirm that RPL26 is a substrate in the liver. Additionally, we discover that mice with the Rpl26 c.395A>G (p.K132R) mutation are more susceptible to steatosis induced by a high-fat diet. Further investigations reveal a key role of CDK5RAP3 and RPL26 UFMylation in regulating ribosome dissociation. Our findings suggest that ribosome UFMylation serves as an important safeguard for liver development and homeostasis and may represent a potential therapeutic target for nonalcoholic fatty liver disease.

Keywords: CP: Metabolism; CP: Molecular biology; UFMylation; liver homeostasis; ribosome.

MeSH terms

Animals
Cell Differentiation*
Hepatocytes* / cytology
Hepatocytes* / metabolism
Homeostasis*
Humans
Liver* / metabolism
Male
Mice
Non-alcoholic Fatty Liver Disease / metabolism
Non-alcoholic Fatty Liver Disease / pathology
Ribosomal Proteins / genetics
Ribosomal Proteins / metabolism
Ribosomes* / metabolism

Substances

Ribosomal Proteins