Volume 32, No 1, Jan 2022

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 32 Issue 1, January 2022: 54-71

ORIGINAL ARTICLES

Nuclear UHRF1 is a gate-keeper of cellular AMPK activity and function

Xiang Xu^1,† , Guangjin Ding^1,2,† , Caizhi Liu^1,† , Yuhan Ding¹ , Xiaoxin Chen¹ , Xiaoli Huang³ , Chen-Song Zhang⁴ , Shanxin Lu⁴ , Yunpeng Zhang¹ , Yuanyong Huang¹ , Zhaosu Chen¹ , Wei Wei¹ , Lujian Liao¹ , Shu-Hai Lin⁴ , Jingya Li⁵ , Wei Liu⁶ , Jiwen Li¹ , Sheng-Cai Lin⁴ , Xinran Ma^1,* , Jiemin Wong^7,*

¹Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
²Zhongshan-Xuhui Hospital, Fudan University and Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
³Department of Biochemistry and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
⁴State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, 4221 South Xiang’an Road, Xiamen, Fujian, China
⁵State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
⁶Department of Biochemistry and Molecular Biology, Program in Molecular and Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
⁷Joint Center for Translational Medicine, Fengxian District Central Hospital, 6600 Nanfeng Road, Shanghai, China
^†These authors contributed equally: Xiang Xu, Guangjin Ding, Caizhi Liu
Correspondence: Xinran Ma(xrma@bio.ecnu.edu.cn)Jiemin Wong(jmweng@bio.ecnu.edu.cn)

The AMP-activated protein kinase (AMPK) is a central regulator of energy homeostasis. Although much has been learned on how low energy status and glucose starvation activate AMPK, how AMPK activity is properly controlled in vivo is still poorly understood. Here we report that UHRF1, an epigenetic regulator highly expressed in proliferating and cancer cells, interacts with AMPK and serves to suppress AMPK activity under both basal and stressed conditions. As a nuclear protein, UHRF1 promotes AMPK nuclear retention and strongly suppresses nuclear AMPK activity toward substrates H2B and EZH2. Importantly, we demonstrate that UHRF1 also robustly inhibits AMPK activity in the cytoplasm compartment, most likely as a consequence of AMPK nucleocytoplasmic shuttling. Mechanistically, we found that UHRF1 has no obvious effect on AMPK activation by upstream kinases LKB1 and CAMKK2 but inhibits AMPK activity by acting as a bridging factor targeting phosphatase PP2A to dephosphorylate AMPK. Hepatic overexpression of UHRF1 showed profound effects on glucose and lipid metabolism in wild-type mice but not in those with the liver-specific knockout of AMPKα1/α2, whereas knockdown of UHRF1 in adipose tissue led to AMPK activation and reduced sizes of adipocytes and lipogenic activity, highlighting the physiological significance of this regulation in glucose and lipid metabolism. Thus, our study identifies UHRF1 as a novel AMPK gate-keeper with critical roles in cellular metabolism.

https://doi.org/10.1038/s41422-021-00565-y

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