J Cell Biol. July 14 2020|Supp Info:https://doi.org/10.1083/jcb.201911036

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CDK4/6 regulate lysosome biogenesis through TFEB/TFE3

Qiuyuan Yin ¹, Youli Jian ², Meng Xu ², Xiahe Huang ², Niya Wang ³, Zhifang Liu ¹, Qian Li ¹, Jinglin Li ¹, Hejiang Zhou ¹, Lin Xu ³, Yingchun Wang ², Chonglin Yang ¹

Abstract

Lysosomes are degradation and signaling organelles that adapt their biogenesis to meet many different cellular demands;however,it is unknown how lysosomes change their numbers for cell division. Here, we report that the cyclin-dependent kinases CDK4/6 regulate  lysosome biogenesis during the cell cycle. Chemical or genetic inactivation of CDK4/6 increases lysosomal numbers by activating the   lysosome and autophagy transcription factors TFEB and TFE3. CDK4/6 interact with and phosphorylate TFEB/TFE3 in the nucleus,    thereby inactivating them by promoting their shuttling to the cytoplasm.During the cell cycle,lysosome numbers increase in S and G2/M phases when cyclin D turnover diminishes CDK4/6 activity. These findings not only uncover the molecular events that direct the      nuclear export of TFEB/TFE3, but also suggest a mechanism that controls lysosome biogenesis in the cell cycle.CDK4/6 inhibitors       promote autophagy and lysosome-dependent degradation, which has important implications for the therapy of cancer and lysosome-     related disorders.