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.
CDK4/6 regulate lysosome biogenesis through TFEB/TFE3
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Qiuyuan Yin, Youli Jian, Meng Xu, Xiahe Huang, Niya Wang, Zhifang Liu, Qian Li, Jinglin Li, Hejiang Zhou, Lin Xu, Yingchun Wang, Chonglin Yang; CDK4/6 regulate lysosome biogenesis through TFEB/TFE3. J Cell Biol 3 August 2020; 219 (8): e201911036. doi: https://doi.org/10.1083/jcb.201911036
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