Every cell in the body relies on a microscopic sorting station—the endosome—to decide whether to reuse a protein or send it for destruction. This project will map the molecular switches that tell the endosome to adapt its sorting decisions when the cell is under stress. The problem is that while scientists know the basic machinery that sorts proteins, they do not understand how that machinery adjusts its behaviour when, for example, a cell is stressed by a buildup of waste in its lysosomes. This gap matters because endosomal sorting failures are increasingly linked to neurodegenerative diseases such as Alzheimer’s and Parkinson’s, where stressed lysosomes and misrouted proteins accumulate together. This is fundamental science. The researchers will use phosphoproteomics—a technique that identifies which proteins have been tagged with phosphate groups—combined with biochemical and computational methods to map these regulatory events. If successful, the work will reveal how lysosomes signal back to endosomes to change sorting priorities. That deeper understanding could eventually point to new targets for drugs aimed at restoring proper protein traffic in neurons, though no immediate clinical application is expected.
View original technical description
Endosomal sorting of integral membrane proteins is essential for cellular homeostasis, determining whether cargo proteins are degraded in lysosomes or recycled back to the plasma membrane and other organelles for reuse. The recycling process is coordinated by endosomal sorting complexes such as ESCPE, Retromer and Commander, which coordinate with cargo adaptors, SNX3, SNX17 and SNX27 and other endosomal proteins to form retrieval subdomains. While the general molecular mechanisms behind cargo sorting are increasingly well understood, regulatory mechanisms governing how endosomes dynamically adapt to cellular needs and environmental stresses remain poorly understood. Yet, defining these mechanisms is crucial, as endosomal dysfunction, especially in concert with lysosomal stress, is increasingly recognized as crucial in the pathogenesis of neurodegenerative diseases. The goal of this project will be to identify key activity-dependent phosphorylation and dephosphorylation events that regulate the function of the endosomal retrieval subdomain, with a specific focus on lysosomal stress induced adaptation. Using phosphoproteomics approaches supplemented with biochemical, cell-based and computational methods, critical regulatory post-translational modifications will be mapped and their function characterized. By defining these regulatory mechanisms, this research will advance our understanding of lysosome-to-endosome signalling and provide insight into the role of endosomal signalling in the pathogenesis of neurodegenerative diseases.
Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.
Is something wrong? Let us know