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Folma Buss

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.

Buss lab LC3 image
Recruitment of myosin VI (green) to autophagosomes (red) in a human epithelial cell. The actin cytoskeleton is labelled in blue

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.

Buss figure 2016 

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.

Buss lab

Key papers:

Masters TA, Tumbarello DA, Chibalina MV, Buss F. MYO6 Regulates Spatial Organization of Signaling Endosomes Driving AKT Activation and Actin Dynamics. Cell Rep. 19, 2088-2101 (2017).

Brooks AB, Humphreys D, Singh V, Davidson AC, Arden SD, Buss F, Koronakis V. MYO6 is targeted by Salmonella virulence effectors to trigger PI3-kinase signaling and pathogen invasion into host cells. Proc. Natl Acad. Sci. USA 114, 3915-3920 (2017).

Masters TA, Buss F. Filopodia formation and endosome clustering induced by mutant plus-end-directed myosin VI. Proc. Natl Acad. Sci. USA 114, 1595-1600 (2017).

Waxse BJ, Sengupta P, Hesketh GG, Lippincott-Schwartz J, Buss F. Myosin VI facilitates connexin 43 gap junction accretion. J. Cell Sci. 130, 827-840 (2017).

Arden SD, Tumbarello DA, Butt T, Kendrick-Jones J, Buss F. Loss of cargo binding in the human myosin VI deafness mutant (R1166X) leads to increased actin filament binding. Biochem J. 473, 3307-3319 (2016).

Kruppa AJ, Kendrick-Jones J, Buss F. Myosins, Actin and Autophagy. Traffic 8, 878-90 (2016).

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, 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).

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).

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).

 

Folma Buss

Dr Folma Buss

University Reader in Molecular and Cellular Dynamics

Department: Clinical Biochemistry

contact:fb207@cam.ac.uk

01223 763348

Plain English

Research in our lab is focused on motor proteins, which are molecular machines that drive cargo along tracks to specific sites in the cell, rather like a train running along a railway network to specific destinations. The cargo is hooked up to the motor with the help of specific adaptor proteins that we have identified in our research. We currently focus on two motors, myosin 1c and myosin VI, which have distinct functions in cell transport. It is important to understand the regulation and on/off switches of these molecular machines, as defects in myosin VI for example can cause deafness and also potentially Parkinson’s disease and prostate cancer. We hope to identify the precise role of myosin VI and its adaptor proteins in neurodegenerative disease, with the hope of devising possible diagnostic and therapeutic strategies.

 

Group members

Sue Arden · Chieko Kishi-Itakura · Antonina Kruppa · Tom O'Loughlin

Funding

British Heart Foundation

Medical Research Council

Biotechnology and Biological Sciences Research Council

Newton Trust