CDK4/6 regulate lysosome biogenesis through TFEB/TFE3

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 c...

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Bibliographic Details
Published in:The Journal of cell biology 2020-08, Vol.219 (8)
Main Authors: Yin, Qiuyuan, Jian, Youli, Xu, Meng, Huang, Xiahe, Wang, Niya, Liu, Zhifang, Li, Qian, Li, Jinglin, Zhou, Hejiang, Xu, Lin, Wang, Yingchun, Yang, Chonglin
Format: Article
Language:English
Subjects:
Active Transport, Cell Nucleus
Autophagy
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism
Biochemistry
Cell Cycle
Cell Nucleus - enzymology
Cell Nucleus - genetics
Cell Proliferation
Cyclin D1 - metabolism
Cyclin-Dependent Kinase 4 - genetics
Cyclin-Dependent Kinase 4 - metabolism
Cyclin-Dependent Kinase 6 - genetics
Cyclin-Dependent Kinase 6 - metabolism
HCT116 Cells
HeLa Cells
Hep G2 Cells
Humans
Lysosomes - enzymology
Lysosomes - genetics
Organelle Biogenesis
Organelles
Phosphorylation
Proteolysis
Signal Transduction
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Summary: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.
ISSN:0021-9525
1540-8140
DOI:10.1083/jcb.201911036