Dr James Edgar

Endosomes are intracellular membrane-bound organelles that have several important roles. Endosomes regulate the trafficking of proteins and lipids between several pathways including the endocytic, secretory, recycling and degradative. As endosomes mature, proteins on the limiting membrane of endosomes can be sorted into domains that tubulate or vesiculate towards the cytosol for recycling. Conversely, proteins can be sorted to domains that subsequently invaginate inwards, away from the cytosol, where they form intralumenal vesicles (ILVs). Once an endosome has acquired ILVs, it becomes termed a late endosome, or multivesicular body (MVB). Trafficking a protein to an ILV has several functions; firstly it removes any signalling capacity of these proteins from interactions with the cytosol (this is especially important for downregulation of activated growth factor receptors), and secondly it packages proteins into vesicles that can be degraded or expelled from the cell.

MVBs have several potential fates. Fusion of an MVB with a lysosome forms a hybrid organelle, an endolysosome, where ILVs and their contents are degraded and recycled. Another fate of MVBs is that they may fuse with the plasma membrane where their ILVs are released into the extracellular milieu - these ILVs now become termed 'exosomes'.

Exosomes are suggested to be involved in intercellular (between different cells) communication and have been implicated in a number of physiological and pathological processes, including antigen presentation, cancer and neurodegeneration. However, the basic cell biology which underlies their biology is relatively poorly understood.

Our lab aims to identify the molecular machinery which governs the behaviour of endosomes and exosomes. MHC-II becomes loaded with peptide in endosomes, and MHC-II is trafficked to ILVs - yet the biological rationale of doing this is not fully understood. We wish to understand what role MVBs play in MHC-II loading and ultimately how they contribute to deliver MHC-II-peptide complexes to the surface of cells.

We have recently shown that in mammalian cells exosomes can be tethered to the plasma membrane of cells following their release. This tethering is dependent upon a protein called tetherin, which plays a similar role in the retention of a number of virions. This highlights the possibility that exosomes have roles in short-range communication, in addition to longer-range communications. Our group will focus on understanding how and why exosomes are retained by this tethering process.