Myosin motor proteins in health and disease
Our aim is to understand how myosin motor proteins such as myosin VI and myosin IC function in intracellular transport processes, cell signalling and membrane dynamics, and how defects in these molecular machines are linked to human diseases. Currently our main objectives are to understand the mechanisms of cargo selection and to delineate the roles of these myosins and their cargo adaptor molecules in autophagy and neurodegenerative disorders.
One of our research focuses is myosin VI, which is a unique retrograde motor that moves along actin filaments and functions in membrane trafficking pathways associated with secretion, endocytosis and autophagy. These diverse roles of myosin VI are mediated by its interaction with a wide range of distinct adaptor proteins that connect it to different cargoes. We are using a variety of cellular, molecular and structural approaches to determine how cargo attaches to and regulates the activity and motor properties of this myosin.
Figure: A. Myosin VI adaptor proteins are required for clearance of cytosolic Salmonella by autophagy; B. Salmonella inside a phagophore; C. In myosin VI-depleted cells cytosolic, ubiquitin-positive Salmonella accumulate inside LC3-positive autophagosomes.
Mutations, overexpression or the absence of myosin VI have been linked to diverse pathological processes such as deafness, cardiomyopathy, astrogliosis and cancer. Currently our main objective is to understand the role of this myosin and its cargo adaptor molecules in autophagy, a critical lysosomal degradation pathway. We have recently established that myosin VI directly interacts with autophagy receptors such as NDP52, optineurin and T6BP and loss of myosin VI activity impairs autophagy.
In another project we focus on myosin 1c, a single-headed myosin of class I, and have demonstrated that it associates with cholesterol-enriched lipid rafts and facilitates their recycling from intracellular compartments to the cell surface. Absence of functional Myo1c causes the accumulation of cholesterol-enriched membranes in the perinuclear recycling compartment and leads to a defect in autophagosome/lysosome fusion.
Tumbarello DA, Manna P, Allen M, Bycroft M, Arden SD, Kendrick-Jones J & Buss F. The autophagy receptor TAX1BP1 and the molecular motor myosin VI are required for clearance of Salmonella typhimurium by autophagy. Plos Pathogens 11, e1005174. doi: 10.1371/journal.ppat.1005174 (2015).
Brandstaetter, H., Kruppa, A.J., Kendrick-Jones, J. and Buss F. Huntingtin is requiredfor ER-to-Golgi transport and for secretory vesicle fusion at the plasma membrane. Disease Models Mech. 7, 1335-40 (2014).
Brandstaetter, H, Kishi-Itakura, C, Manstein D, Tumbarello D. and Buss F. Loss of functional myosin 1c, a motor protein involved in lipid raft trafficking, disrupts autophagosome-lysosome fusion. Autophagy 10, 2310-23 (2014).
Tumbarello, D. A., Kendrick-Jones, J. and Buss, F. Myosin VI and its cargo adaptors — linking endocytosis and autophagy. J. Cell Sci. 126, 2561–2570 (2013).
Tomatis, V. M., Malintan, N. T., Wallis, T. P., Gormal, R.,Papadopulos, A., Martin, S., Kendrick‑Jones, J., Buss,F. and Meunier,F. A. Myosin-VI Small Insert mediates activity-dependent recruitment of neurosecretory vesicles to F-actin. J. Cell Biol. 200, 301–320 (2013).
Tumbarello, D. A., Waxse, B. J., Arden, S. D., Bright, N. A., Kendrick-Jones, J. and Buss, F. Autophagy-receptors link myosin VI to autophagosomes to mediate Tom1-dependent autophagosome maturation and fusion with the lysosome. Nature Cell Biol. 10, 1024–1035 (2012).
Heisler, S. M., Selvadurai, J., Bond, L. M., Fedorov, R., Kendrick-Jones, J., Buss, F. and Manstein, D. J. Kinetic Properties and Small-Molecule Inhibition of Human Myosin-6. FEBS Lett. 586, 3208–3214 (2012).
Brandstaetter,H., Kendrick-Jones, J. and Buss,F. Myo1c regulates lipid raft recycling to control cell spreading, migration and Salmonella invasion J. Cell Sci. 125, 1991–2003 (2012).
Bond, L. M., Peden, A. A., Kendrick-Jones, J., Sellers, J. R. and Buss, F. Myosin VI and its binding partner optineurin are novel players in secretory vesicle fusion at the plasma membrane. Mol. Biol. Cell 22, 54–66 (2011).
Chibalina, M. V., Poliakov, A., Kendrick-Jones, J. and Buss, F. Myosin VI and optineurin are required for polarised EGFR delivery and directed migration. Traffic 10, 1290–1303 (2010).