Autophagy receptors link myosin VI to autophagosomes to mediate Tom1-dependent autophagosome maturation and fusion with the lysosome

Nat Cell Biol. 2012 Oct;14(10):1024-35. doi: 10.1038/ncb2589. Epub 2012 Sep 30.

Abstract

Autophagy targets pathogens, damaged organelles and protein aggregates for lysosomal degradation. These ubiquitylated cargoes are recognized by specific autophagy receptors, which recruit LC3-positive membranes to form autophagosomes. Subsequently, autophagosomes fuse with endosomes and lysosomes, thus facilitating degradation of their content; however, the machinery that targets and mediates fusion of these organelles with autophagosomes remains to be established. Here we demonstrate that myosin VI, in concert with its adaptor proteins NDP52, optineurin, T6BP and Tom1, plays a crucial role in autophagy. We identify Tom1 as a myosin VI binding partner on endosomes, and demonstrate that loss of myosin VI and Tom1 reduces autophagosomal delivery of endocytic cargo and causes a block in autophagosome-lysosome fusion. We propose that myosin VI delivers endosomal membranes containing Tom1 to autophagosomes by docking to NDP52, T6BP and optineurin, thereby promoting autophagosome maturation and thus driving fusion with lysosomes.

MeSH terms

  • Autophagy / physiology*
  • Endosomes / physiology
  • HeLa Cells
  • Humans
  • Intracellular Membranes / physiology
  • Lysosomes / physiology*
  • Membrane Fusion / physiology
  • Myosin Heavy Chains / physiology*
  • Nuclear Proteins / physiology
  • Phagosomes / physiology*
  • Proteins / physiology*
  • Transcription Factor TFIIIA / physiology

Substances

  • CALCOCO2 protein, human
  • Nuclear Proteins
  • OPTN protein, human
  • Proteins
  • TOM1 protein, human
  • Transcription Factor TFIIIA
  • myosin VI
  • Myosin Heavy Chains