Transport of proteins throughout the cell is a highly regulated process that is a fundamental aspect of cell biology. The endosomal protein recycling pathway is one important cellular transport process which promotes the rescue of proteins destined for degradation in the lysosome by recycling them back to the Golgi or plasma membrane from endosomes. A major contributor to this fundamental cellular process is the WASH protein. WASH is part of the WASP family of actin nucleation promoting factors and specifically promotes actin assembly on endosomes to facilitate protein recycling. Importantly, WASH and endosomal protein recycling have been linked to a number of human diseases, including hereditary sporadic paraplegia, Alzheimer's, and cancer. Furthermore, this cellular process is required for the transport of lethal pathogenic toxins, such as cholera, ricin, and anthrax to their site of action. Therefore, understanding the function and regulation of WASH has important implication on human health. WASH is held in an auto-inhibited state due to its incorporation into a multi-subunit complex, referred to as the WASH regulatory complex or SHRC. Recently, it was described that WASH is activated by ubiquitination. Ubiquitination is a post-translational modification that can alter the stability, confirmation, and/or activity of protins in cells. Non-canonical K63-linked ubiquitination of WASH by the MAGE-L2-TRIM27 E3 ubiquitin ligase is an essential event in WASH activation, generation of endosomal F-actin, and endosomal protein recycling. Utilizing a number of in vitro biochemical and cellular approaches, this project aims to determine the mechanisms and signaling pathways regulating WASH activity through post-translational modifications. Furthermore, it aims to determine the physiological functions of WASH and MAGE-L2-TRIM27 with emphasis on their disease-related functions. These studies are important for our understanding of WASH-mediated endosomal protein recycling, breaking critical barriers to treating human diseases associated with manipulation of this cellular process, and advancing our scientific knowledge of this fundamental cellular process.
Endosomal protein recycling is an essential cellular process that mediates the sorting of proteins in cells to regulate their localization, abundance, and activity. Alterations in this fundamental cellular process have been linked to a number of human diseases, including cancer, hereditary sporadic paralysis, Prader-Willi syndrome, and Alzheimer's disease. This project seeks to understand the molecular mechanisms regulating this pathway and how detrimental pathological conditions develop upon its disruption.
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| Lee, Anna K; Potts, Patrick Ryan (2017) A Comprehensive Guide to the MAGE Family of Ubiquitin Ligases. J Mol Biol 429:1114-1142 |
| Weon, Jenny L; Potts, Patrick Ryan (2015) The MAGE protein family and cancer. Curr Opin Cell Biol 37:1-8 |
| Hao, Yi-Heng; Fountain Jr, Michael D; Fon Tacer, Klementina et al. (2015) USP7 Acts as a Molecular Rheostat to Promote WASH-Dependent Endosomal Protein Recycling and Is Mutated in a Human Neurodevelopmental Disorder. Mol Cell 59:956-69 |
