Understanding the Role of Transporters and Ion Channels in Lysosomal Homeostasis

Cellular activity is regulated based on a range of signals to maintain homeostasis. The lysosome plays an essential role in this process as it can regulate nutrient levels since it is the main site of biomolecule degradation in the cell and it can regulate cell signaling as it is a site for the activation of signaling proteins involved in maintaining cellular homeostasis. These regulatory functions require optimal lysosomal protein activity, which can be affected by the lysosomal pH and membrane potential, and ion and nutrient levels. Nutrient levels in the lysosome are regulated by efflux transporters that provide nutrients for cellular activity and prevent the deleterious accumulation of nutrients. The mechanism of some of these transporters remain to be characterized. Characterizing their mechanism will enable to understand how changes in the lysosomal environment may impact their activity and vice versa. This is critical to understand their role in lysosomal homeostasis. Aim 1 of this project will be to characterize the mechanism of a transporter that is essential to maintain lysosomal homeostasis. Cell signaling at the lysosomal membrane also plays a critical role in maintaining lysosomal and cellular homeostasis by regulating the activity of the proteins on the lysosomal surface and the expression of genes involved in lysosome formation, repair and activity. New regulators of these signaling pathways have been identified, but their mechanisms remain poorly characterized. Aim 2 of this project will involve the development of a novel proteomics method to characterize the interactions formed by these regulators and understand their mechanism of action. Overall, this work will provide novel insights into the mechanism of a key lysosomal transporter and regulators of lysosomal signaling, which are essential to preserve lysosomal and cellular homeostasis.

BBSRC priority areas: Technology development for the biosciences and Data driven biology.