The presence of intracellular membrane-bound compartments, or organelles, is a defining feature of eukaryotic cells. Organelles allow the compartmentalization of material or reactions within the eukaryotic cell. However, this feature creates a logistical problem concerning how these distinct entities are generated and maintained.
The multivesicular body (MVB) is an extremely interesting organelle formed by the budding of intralumenal vesicles (ILVs) into an endosome. This process allows the sequestration of transmembrane proteins and cytoplasmic factors away from the cytoplasm for degradation within the lysosome or for eventual release from the cell in extracellular vesicles (exosomes). The canonical machinery facilitating MVB formation is the endosomal sorting complexes required for transport (ESCRTs).
For nearly 20 years our group has been interested in how the ESCRTs and associated factors facilitate the MVB sorting process. Our work has helped identify how proteins are marked for entry into this pathway, how the ESCRTs machinery recognizes these MVB cargoes, and how the dynamics of ESCRTs assembly are regulated to facilitate ILVformation.
We have traditionally investigated these processes using the yeast model system Saccharomyces cerevisiae in conjunction with biochemical and structural biology approaches. While these efforts continue to this day, we have also used our insights from yeast to explore the process of exosome release and communication in human polarized epithelia of the bile duct (cholangiocytes) as well as to investigate the impacts on mammalian physiology of partial ESCRTs dysfunction using a hypomorphic HD-PTP mouse model.