Departments and Institutes
I aim to understand how myosin motor proteins - such as myosin VI and myosin 1C - function in intracellular transport processes, cell signalling and membrane dynamics, and how defects in these molecular machines are linked to human diseases.
Myosin VI 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.
Mutations, overexpression, or the absence of myosin VI have been linked to diverse pathological processes such as cancer, cardiomyopathy and deafness. 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 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 protein causes the accumulation of cholesterol-enriched membranes in the perinuclear recycling compartment and leads to a defect in autophagosome/lysosome fusion.
intracellular transport ; autophagy
Loss of cargo binding in the human myosin VI deafness mutant (R1166X) leads to increased actin filament binding. Arden SD, Tumbarello DA, Butt T, Kendrick-Jones J, Buss F. Biochem J. 2016 Oct 1;473(19):3307-19.
The Autophagy Receptor TAX1BP1 and the Molecular Motor Myosin VI Are Required for Clearance of Salmonella Typhimurium by Autophagy. Tumbarello DA, Manna PT, Allen M, Bycroft M, Arden SD, Kendrick-Jones J, Buss F. PLoS Pathog. 2015 Oct 9;11(10):e1005174.
Loss of functional MYO1C/myosin 1c, a motor protein involved in lipid raft trafficking, disrupts autophagosome-lysosome fusion. Brandstaetter H, Kishi-Itakura C, Tumbarello DA, Manstein DJ, Buss F. Autophagy. 2014 Dec 31:0.
Huntingtin is required for ER-to-Golgi transport and for secretory vesicle fusion at the plasma membrane. Brandstaetter H, Kruppa AJ, Buss F. Dis Model Mech. 2014 Dec;7(12):1335-40.
Myosin VI and its cargo adaptors - linking endocytosis and autophagy. Tumbarello DA, Kendrick-Jones J, Buss F. J Cell Sci. 2013 Jun 15;126(Pt 12):2561-70.
Myosin VI small insert isoform maintains exocytosis by tethering secretory granules to the cortical actin. Tomatis VM, Papadopulos A, Malintan NT, Martin S, Wallis T, Gormal RS, Kendrick-Jones J, Buss F, Meunier FA. J Cell Biol. 2013 Feb 4;200(3):301-20.
Autophagy receptors link myosin VI to autophagosomes to mediate Tom1-dependent autophagosome maturation and fusion with the lysosome. Tumbarello DA, Waxse BJ, Arden SD, Bright NA, Kendrick-Jones J, Buss F. Nat Cell Biol. 2012 Oct;14(10):1024-35.
Functional roles for myosin 1c in cellular signaling pathways. Bond LM, Brandstaetter H, Kendrick-Jones J, Buss F. Cell Signal. 2013 Jan;25(1):229-35.
Dynamic exchange of myosin VI on endocytic structures. Bond LM, Arden SD, Kendrick-Jones J, Buss F, Sellers JR. J Biol Chem. 2012 Nov 9;287(46):38637-46.
More publications available through PubMed.