VPS34 K29/K48 branched ubiquitination governed by UBE3C and TRABID regulates autophagy, proteostasis and liver metabolism

Yu-Hsuan Chen, Tzu-Yu Huang, Yu-Tung Lin, Shu-Yu Lin, Wen-Hsin Li, Hsiang-Jung Hsiao, Ruei-Liang Yan, Hong-Wen Tang, Zhao-Qing Shen, Guang-Chao Chen, Kuen-Phon Wu, Ting-Fen Tsai and Ruey-Hwa Chen ()
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Yu-Hsuan Chen: Institute of Biological Chemistry, Academia Sinica
Tzu-Yu Huang: Institute of Biological Chemistry, Academia Sinica
Yu-Tung Lin: Institute of Biological Chemistry, Academia Sinica
Shu-Yu Lin: Institute of Biological Chemistry, Academia Sinica
Wen-Hsin Li: Institute of Biological Chemistry, Academia Sinica
Hsiang-Jung Hsiao: Institute of Biological Chemistry, Academia Sinica
Ruei-Liang Yan: Institute of Biological Chemistry, Academia Sinica
Hong-Wen Tang: Institute of Biological Chemistry, Academia Sinica
Zhao-Qing Shen: National Yang-Ming University
Guang-Chao Chen: Institute of Biological Chemistry, Academia Sinica
Kuen-Phon Wu: Institute of Biological Chemistry, Academia Sinica
Ting-Fen Tsai: National Yang-Ming University
Ruey-Hwa Chen: Institute of Biological Chemistry, Academia Sinica

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: Abstract The ubiquitin–proteasome system (UPS) and autophagy are two major quality control processes whose impairment is linked to a wide variety of diseases. The coordination between UPS and autophagy remains incompletely understood. Here, we show that ubiquitin ligase UBE3C and deubiquitinating enzyme TRABID reciprocally regulate K29/K48-branched ubiquitination of VPS34. We find that this ubiquitination enhances the binding of VPS34 to proteasomes for degradation, thereby suppressing autophagosome formation and maturation. Under ER and proteotoxic stresses, UBE3C recruitment to phagophores is compromised with a concomitant increase of its association with proteasomes. This switch attenuates the action of UBE3C on VPS34, thereby elevating autophagy activity to facilitate proteostasis, ER quality control and cell survival. Specifically in the liver, we show that TRABID-mediated VPS34 stabilization is critical for lipid metabolism and is downregulated during the pathogenesis of steatosis. This study identifies a ubiquitination type on VPS34 and elucidates its cellular fate and physiological functions in proteostasis and liver metabolism.

Date: 2021
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DOI: 10.1038/s41467-021-21715-1

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