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

作　　者：Xiang Xu Guangjin Ding Caizhi Liu Yuhan Ding Xiaoxin Chen Xiaoli Huang Chen-Song Zhang Shanxin Lu Yunpeng Zhang Yuanyong Huang Zhaosu Chen Wei Wei Lujian Liao Shu-Hai Lin Jingya Li Wei Liu Jiwen Li Sheng-Cai Lin Xinran Ma Jiemin Wong 

机构地区：[1]Shanghai Key Laboratory of Regulatory Biology,Institute of Biomedical Sciences and School of Life Sciences,East China Normal University,Shanghai,China [2]Zhongshan-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 [3]Department of Biochemistry and Department of Cardiology of the Second Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou,Zhejiang,China [4]State 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 [5]State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,University of Chinese Academy of Sciences,Chinese Academy of Sciences,Shanghai,China [6]Department of Biochemistry and Molecular Biology,Program in Molecular and Cell Biology,Zhejiang University School of Medicine,Hangzhou,Zhejiang,China [7]Joint Center for Translational Medicine,Fengxian District Central Hospital,6600 Nanfeng Road,Shanghai,China

出　　处：《Cell Research》2022年第1期54-71,共18页细胞研究（英文版）

基　　金：supported by grants from the Ministry of Science and Technology of China(2017YFA054201);the National Natural Science Foundation of China(31730048 and 31961133009 to J.W.);Shanghai Science and Technology Committee(20JC1411500 to J.W.);the National Natural Science Foundation of China(91957120 to S.H.L).

摘　　要：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.

关 键 词：METABOLISM UHRF1 AMPK 

分 类 号：R329.2[医药卫生—人体解剖和组织胚胎学]