An essential role for chaperone-mediated autophagy in cell cycle progression

Hypoxia has long been known to serve as a stimulus for cell cycle arrest. Hypoxia-mediated cell cycle arrest is mediated through the actions of HIF1α (hypoxia inducible factor 1, α subunit [basic helix-loop-helix transcription factor]), which has a nontranscriptional role as an inhibitor of MCM (minichromosome maintenance complex component) helicase activity.We identified chaperone-mediated autophagy as a pathway for selective degradation of HIF1α through lysosomes prior to the onset of DNA replication. CDK2 (cyclin-dependent kinase 2) mediates degradation of HIF1α at the G₁/S transition, whereas CDK1 (cyclin-dependent kinase 1) increases HIF1α levels and transcriptional activity prior to the onset of G₁ phase. Lysosomal inhibitors induce cell cycle arrest, which is recovered by knockdown ofHIF1a and EPAS1/HIF2α. These findings establish lysosomes as essential regulators of cell cycle progression through the degradation of HIF1α.