J Cell Biol. July 14 2020|Supp Info:

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


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.