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

溶酶体作为细胞降解和信号中心，协调细胞对营养物质和激素或生长因子等信号的代谢。细胞溶酶体的含量和对大分子的降解能力是由转录因子如TFEB/ TFE3来调节的，这些转录因子激活了编码溶酶体蛋白和自噬因子的基因的表达。溶酶体和自噬基因的转录激活可由多种条件诱导，如饥饿、溶酶体应激和溶酶体储存障碍。这些不同的线索是如何整合在一起的，目前还不完全清楚。在我们的初步工作中，我们已经确定了一条在质膜上启动的途径，该途径控制细胞溶酶体和自噬体的含量，从而通过胞内离子稳态的内吞调节来控制降解能力。这一途径似乎是基于NHE7的外胞吞作用，NHE7是一种在人类x连锁智力残疾中突变的Na+/ H+交换体。我们假设，Na+/ H+交换剂NHE7在质膜上的移除和传递在响应刺激（如高渗或蛋白质毒性应激）时，通过转录因子如TFEB/ TFE3控制自噬/溶酶体的生物发生，在有效清除蛋白质聚集体方面起着至关重要的（病理）生理功能。该项目的总体目标是从分子上确定渗透应激和/或其他刺激如何调节NHE7外/内吞作用以改变细胞内离子稳态，从而控制溶酶体和自噬体的生物发生和功能，以及这可能与人类疾病的关系。

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.