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

Nature Cell Biology volume 14, pages 1024–1035 (2012)Cite this article

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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.

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Figure 1: Loss of myosin VI function leads to an accumulation of autophagosomes.
Figure 2: Myosin VI is required for autophagosomal degradation of huntingtin- and p62-positive protein aggregates.
Figure 3: Myosin VI localizes to LC3-positive autophagosomes.
Figure 4: Myosin VI targets to autophagosomes through the RRL motif in the cargo-binding tail domain.
Figure 5: The myosin VI binding partners T6BP, NDP52 and optineurin co-localize with myosin VI on autophagosomes and are required for autophagosome biogenesis.
Figure 6: Tom1 interacts with myosin VI and is required for myosin VI localization to endosomes.
Figure 7: Loss of Tom1 inhibits the maturation of autophagosomes and their subsequent fusion with lysosomes.
Figure 8: Myosin VI mediates delivery of endocytic cargo to autophagosomes.

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Acknowledgements

This work was financially supported by the Wellcome Trust (F.B., D.A.T. and S.D.A.), the Medical Research Council (J.K-J. and N.A.B.) and a NIH-Oxford-Cambridge Ph.D. studentship (B.J.W.). The CIMR is in receipt of a strategic award from the Wellcome Trust (079895). We thank M. Seaman, F. Randow, L. Wartosch, D. Rubinsztein and D. Owen for critical reading of the manuscript and helpful discussions.

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  1. Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK

    David A. Tumbarello, Bennett J. Waxse, Susan D. Arden, Nicholas A. Bright & Folma Buss

  2. MRC Laboratory of Molecular Biology, Cambridge, CB2 0QH, UK

    John Kendrick-Jones

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Contributions

D.A.T. designed and performed experiments, analysed the data and wrote the manuscript. B.J.W. performed live-cell video microscopy and S.D.A. performed mammalian two-hybrid assays. N.A.B. performed electron microscopy experiments. J.K-J. gave technical advice and edited the manuscript. F.B. conceived the study, designed the experiments and wrote the manuscript.

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Correspondence to David A. Tumbarello or Folma Buss.

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Tumbarello, D., Waxse, B., Arden, S. et al. Autophagy receptors link myosin VI to autophagosomes to mediate Tom1-dependent autophagosome maturation and fusion with the lysosome. Nat Cell Biol 14, 1024–1035 (2012). https://doi.org/10.1038/ncb2589

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