The role of molecular chaperones in mammalian primary cilia structure and function

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Many cells in the human body have sensory antennae, known as primary cilia, projecting from their surface. Primary cilia function to help cells sense their environment and are linked to molecular pathways which communicate changes in the extra-cellular environment to other cells. Primary cilia play a role in many different systems and are important for sensing both the external environment and maintaining homeostasis (equilibrium of the bodies systems) within the organism. For example, on the surface of cells responsible for smell, odour receptors are located at the primary cilia; furthermore they are essential for vision as photoreceptor, the cells type at the back of the eye which detect light, have a specialised primary cilia structure. Primary cilia are also found on the surface of cells lining tubules in the kidney where they detect the flow of fluid. Unsurprisingly compromised primary cilia structure and/or function can cause disorders such as blindness and kidney disease. Recently it has also been recognised that defects in primary cilia function may be linked to much more common health problems such as obesity, diabetes and high blood pressure. Thus it is important to fully understand how primary cilia work and the processes involved in their construction and maintenance. This application aims to elucidate such processes. Proteins are the essential biological molecules that build the machines which allow the body function. Most proteins work in multi-protein complexes. Clues as to which proteins may play a role in primary cilia function have come from a range of experimental techniques including models of disease and screens that have attempted to define all of the proteins present in motile cilia (another type of cilia which have a different internal structure and perform different functions). Members of a class of proteins known as molecular chaperones have consistently been identified as important for normal cilia function. Molecular chaperones help other proteins perform their functions. One key cellular role of molecular chaperones is to help other proteins assemble into multi-protein complexes. I hypothesise that molecular chaperones are important for assembly of such multi-protein complexes in primary cilia. This proposal aims to identify which molecular chaperones are present in primary cilia and define their roles. Molecular chaperone do not function in isolation, but work together in molecular 'machines'. Multiple components of the Hsp70 molecular chaperone machine are predicted to be present in primary cilia and it is on this molecular chaperone system that we will focus. To find out more about the Hsp70 molecular chaperone machinery and understand what it does in primary cilia we will perform a comprehensive series of experiments. These will identifying which molecular chaperones are present in primary cilia, where precisely they are located in the structure, which proteins they interact with and what happens to primary cilia when they are absent. Completing these goals will advance our understanding of the cellular roles of molecular chaperones. It will also identify proteins which are important for primary cilia function; some of these may be important for human disease and/or represent targets for therapeutic intervention in human disease such as obesity.