Endosomal retrieval sub-domain organisation, dynamics and function in human health and disease (360G-Wellcome-319367_Z_24_Z)

In eukaryotic cells, the endosomal network is a hub of organelles that orchestrates the dynamic sorting of thousands of integral cargo proteins to maintain cellular homeostasis. On entering the network cargo are sorted between two fates: either transport to lysosomes for degradation and loss to the cell or they undergo retrieval and recycling for reuse at target organelles that include the cell surface, the autophagic and biosynthetic pathways, and specialized lysosome-related organelles. We have identified many of the key protein complexes essential for endosomal cargo retrieval and recycling and established that endosome function requires these proteins to coalescence into a specialised nanoscale region of the endosomal membrane, the retrieval sub-domain. But mechanistically how these proteins really “work” remains largely unknown, precluding our understanding of how recycling is altered in human disease. In the current collaborative proposal, we will integrate cutting-edge enabling technologies across spatial and temporal scales to address the organization, dynamics and regulation of the human retrieval sub-domain and how this is integrated with the maintenance of lysosomal health and homeostasis. By applying acquired knowledge we seek to understand how defects in the retrieval sub-domain are linked with developmental and age-related neurodegenerative disease, cancer, metabolic syndrome and host:pathogen interactions.