Mechanism of regulation of lysosome biogenesis and function by cellular ion homeostasis

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Lysosomes serve as cellular degradation and signaling centers that coordinate cell metabolism in response to nutrients and signals such as hormones or growth factors. Cellular lysosome content and degradative capacity for macromolecules are adapted to cellular needs by transcription factors such as TFEB/ TFE3 that activate the expression of genes encoding lysosomal proteins and autophagy factors. Transcription activation of lysosome and autophagy genes is induced by a variety of conditions such as starvation, lysosome stress, and lysosomal storage disorders. How these various cues are integrated remains incompletely understood. In our preliminary work we have identified a pathway initiated at the plasma membrane that controls cellular lysosome and autophagosome content and, thereby, degradative capacity via the endocytic regulation of intracellular ion homeostasis. This pathway appears to be based on the exo-endocytosis of NHE7, a Na+/ H+ exchanger mutated in X-linked intellectual disability in humans. We hypothesize that the regulated removal and delivery of the Na+/ H+ exchanger NHE7 from and to the plasma membrane plays a crucial (patho-)physiological function in the efficient clearance of protein aggregates in response to stimuli (e.g. hyperosmotic or proteotoxic stress) by controlling autophagy/ lysosome biogenesis via transcription factors such as TFEB/ TFE3. The overall objective of the project is to molecularly define how osmotic stress and/ or other stimuli regulate NHE7 exo-/ endocytosis to alter intracellular ion homeostasis and, thereby, control the biogenesis and function of lysosomes and autophagosomes and how this may relate to human disease.