Regulation of energy homeostasis by the ubiquitin-independent REGγ proteasome

Lianhui Sun, Guangjian Fan, Peipei Shan, Xiaoying Qiu, Shuxian Dong, Lujian Liao, Chunlei Yu, Tingting Wang, Xiaoyang Gu, Qian Li, Xiaoyu Song, Liu Cao, Xiaotao Li, Yongping Cui, Shengping Zhang () and Chuangui Wang ()
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Lianhui Sun: Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
Guangjian Fan: Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
Peipei Shan: Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
Xiaoying Qiu: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University
Shuxian Dong: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University
Lujian Liao: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University
Chunlei Yu: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University
Tingting Wang: Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
Xiaoyang Gu: Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
Qian Li: School of Life Science & Technology, China Pharmaceutical University
Xiaoyu Song: Key Laboratory of Medical Cell Biology, College of Translational Medicine, China Medical University
Liu Cao: Key Laboratory of Medical Cell Biology, College of Translational Medicine, China Medical University
Xiaotao Li: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University
Yongping Cui: Key Laboratory of Cellular Physiology Ministry of Education, Shanxi Medical University
Shengping Zhang: Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
Chuangui Wang: Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: Abstract Maintenance of energy homeostasis is essential for cell survival. Here, we report that the ATP- and ubiquitin-independent REGγ-proteasome system plays a role in maintaining energy homeostasis and cell survival during energy starvation via repressing rDNA transcription, a major intracellular energy-consuming process. Mechanistically, REGγ-proteasome limits cellular rDNA transcription and energy consumption by targeting the rDNA transcription activator SirT7 for ubiquitin-independent degradation under normal conditions. Moreover, energy starvation induces an AMPK-directed SirT7 phosphorylation and subsequent REGγ-dependent SirT7 subcellular redistribution and degradation, thereby further reducing rDNA transcription to save energy to overcome cell death. Energy starvation is a promising strategy for cancer therapy. Our report also shows that REGγ knockdown markedly improves the anti-tumour activity of energy metabolism inhibitors in mice. Our results underscore a control mechanism for an ubiquitin-independent process in maintaining energy homeostasis and cell viability under starvation conditions, suggesting that REGγ-proteasome inhibition has a potential to provide tumour-starving benefits.

Date: 2016
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DOI: 10.1038/ncomms12497

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