CDK4/6 regulate lysosome biogenesis through TFEB/TFE3

J Cell Biol. 2020 Aug 3;219(8):e201911036. doi: 10.1083/jcb.201911036.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Autophagy
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
  • 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*
  • Phosphorylation
  • Proteolysis
  • Signal Transduction

Substances

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • CCND1 protein, human
  • TFE3 protein, human
  • TFEB protein, human
  • Cyclin D1
  • CDK4 protein, human
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6