title: Autophagy receptors link myosin VI to autophagosomes to mediate Tom1-dependent autophagosome maturation and fusion with the lysosome.
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.
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK. dat39@cam.ac.uk
authors.forename: David A
authors.initials: DA
authors.lastname: Tumbarello
authors.forename: Bennett J
authors.initials: BJ
authors.lastname: Waxse
authors.forename: Susan D
authors.initials: SD
authors.lastname: Arden
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Bright
authors.forename: John
authors.initials: J
authors.lastname: Kendrick-Jones
authors.forename: Folma
authors.initials: F
authors.lastname: Buss
mesh_terms: D001343:Autophagy / Q000502:physiology*; D018797:Cell Cycle Proteins; D011992:Endosomes / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D007425:Intracellular Membranes / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D008247:Lysosomes / Q000502:physiology*; D008561:Membrane Fusion / Q000502:physiology; D026901:Membrane Transport Proteins; D018995:Myosin Heavy Chains / Q000502:physiology*; D009687:Nuclear Proteins / Q000502:physiology; D010588:Phagosomes / Q000502:physiology*; D011506:Proteins / Q000502:physiology*; D035582:Transcription Factor TFIIIA / Q000502:physiology
chemical_list: C094297:CALCOCO2 protein, human; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D026901:Membrane Transport Proteins; D009687:Nuclear Proteins; C409460:OPTN protein, human; D011506:Proteins; C120296:TOM1 protein, human; D035582:Transcription Factor TFIIIA; C089785:myosin VI; D018995:Myosin Heavy Chains