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

Abstract

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.

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Fig. 1: UHRF1 interacts with and negatively controls AMPK activity.
Fig. 2: UHRF1 restrains stress-induced AMPK activation and promotes lipid synthesis and glycolysis through inhibiting AMPK.
Fig. 3: Nuclear UHRF1 robustly suppresses AMPK activity in both the nucleus and cytoplasm.
Fig. 4: UHRF1 suppresses AMPK activity by promoting PP2A dependent dephosphorylation.
Fig. 5: The nuclear UHRF1/AMPK/PP2A complexes and resistance of lysosome-anchored AMPKα to UHRF1-mediated dephosphorylation.
Fig. 6: UHRF1 regulates glucose and lipid metabolism in mice.
Fig. 7: UHRF1 regulates glucose and lipid metabolism in mice through AMPK.

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Acknowledgements

We thank all other members of the J.W. laboratory for suggestions and technical assistance. We thank Q.Y. Lei (Fudan University, Shanghai, China) for kindly providing the AMPKα1/α2 double-knockout MEFs. We thank X.H. Feng (Zhejiang University, Hangzhou, China) for kindly providing FLAG-PPP2CA, FLAG-PP2Cα, FLAG-PP2Cβ and FLAG-PPM1E expression constructs. We also thank Wen Chen (Sun Yat-sen University, Guangzhou, China) for kindly providing antibody and shRNA plasmid for PPP2R5D. This study is supported by grants from the Ministry of Science and Technology of China (2017YFA054201) and the National Natural Science Foundation of China (31730048 and 31961133009 to J.W.), the Shanghai Science and Technology Committee (20JC1411500 to J.W.) and the National Natural Science Foundation of China (91957120 to S.H.L.).

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The study was designed by X.X., G.D., X.M. and J.W., all biochemical and most cellular experiments were performed by X.X., G.D., Y.D., X.H., Y.H. and Z.C.; X.H., X.X., W.W., and W.L. did live cell imaging experiments. C.L., X.C. and J.L. carried out experiments with liver-specific UHRF1 overexpression and liver-specific AMPKα1/α2 knockout mice. X.X., G.D., C.L., X.M. and J.W. wrote the manuscript and all members edited the manuscript.

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Correspondence to Xinran Ma or Jiemin Wong.

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Xu, X., Ding, G., Liu, C. et al. Nuclear UHRF1 is a gate-keeper of cellular AMPK activity and function. Cell Res (2021). https://doi.org/10.1038/s41422-021-00565-y

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