Dr. Folma Buss, Cambridge Institute for Medical Research (CIMR), University of Cambridge
Tuesday 7th February, 1.00 p.m., Stacey Lecture Theatre 1
In eukaryotic cells, a multitude of motor proteins have evolved, each designed to carry specific cargo along actin filaments and microtubules under precise regulatory control to distinct cellular compartments. The focus of my lab is to establish how myosin motor proteins such as MYO6, MYO9B and MYO1C function in intracellular transport processes, cell signalling and membrane dynamics, and how defects in these molecular machines are linked to human diseases. Currently one of our main objectives is to understand the mechanisms of cargo selection and to delineate the roles of these myosins and their cargo adaptor molecules in cytokine secretion and autophagy linked to chronic inflammation, neurodegenerative disorders, innate immunity as well as heart disease.
To understand the spatial and temporal regulation of motor/cargo attachment and to identify the complete motor protein interactome under different physiological conditions in different cell types, we have used a combination of proteomic methods including novel in-situ proximity labelling strategies as well as more traditional affinity purification methods. Using these approaches we have identified a multitude of novel MYO6-associated proteins, which we can group into multiple distinct protein complexes that link MYO6 to actin filament regulation, membrane trafficking and distinct signalling cascades.
Autophagy is an essential intracellular degradation pathway that delivers cytoplasmic components to the lysosome for degradation. Defective autophagy is linked to many human diseases including cancer and neurodegeneration. MYO6, in concert with its adaptor proteins/selective autophagy receptors NDP52, OPTN and TAX1BP1 plays a crucial role in autophagosome maturation and fusion with lysosomes. In this pathway MYO6 is required for autophagosomal clearance of cytosolic bacteria, misfolded protein aggregates and dysfunctional mitochondria. We are currently analysing the exact role of MYO6 and the actin cytoskeleton during autophagy using animal models and high-resolution live cell as well as electron microscopy.
In addition our most recent results have provided strong evidence that different classes of myosin motors have distinct functions in protein secretion and selectively regulate release of different cytokines that have been linked to the development of human chronic inflammatory diseases. Myosin motors are attractive drug targets and in collaboration with computational chemists we aim to develop novel compounds, which can be used to investigate the role of different classes myosins in cytokine exocytosis and validate myosins as targets for future drug development.