Lysosomes serve as cellular degradation and signalling centres that coordinate metabolism in response to intracellular cues and extracellular signals. Lysosomal capacity is adapted to cellular needs by transcription factors, such as TFEB and TFE3, which activate the expression of lysosomal and autophagy genes. Nuclear translocation and activation of TFEB are induced by a variety of conditions such as starvation, lysosome stress and lysosomal storage disorders. How these various cues are integrated remains incompletely understood. Here, we describe a pathway initiated at the plasma membrane that controls lysosome biogenesis via the endocytic regulation of intracellular ion homeostasis. This pathway is based on the exo-endocytosis of NHE7, a Na⁺/H⁺ exchanger mutated in X-linked intellectual disability, and serves to control intracellular ion homeostasis and thereby Ca²⁺/calcineurin-mediated activation of TFEB and downstream lysosome biogenesis in response to osmotic stress to promote the turnover of toxic proteins and cell survival.

溶酶体作为细胞降解和信号中心，协调代谢以响应细胞内信号和细胞外信号。溶酶体容量通过转录因子（如 TFEB 和 TFE3）适应细胞需求，这些转录因子激活溶酶体和自噬基因的表达。TFEB 的核转位和激活是由多种条件诱导的，例如饥饿、溶酶体应激和溶酶体贮积障碍。如何整合这些不同的线索仍然不完全清楚。在这里，我们描述了一种在质膜上启动的途径，该途径通过细胞内离子稳态的内吞调节来控制溶酶体的生物发生。该途径基于 NHE7 的胞外吞作用，一个 Na ⁺ /H ⁺X连锁智力障碍中发生突变的交换器，用于控制细胞内离子稳态，从而控制Ca ²⁺ /钙调神经磷酸酶介导的TFEB活化和下游溶酶体生物合成，以响应渗透压，促进有毒蛋白质的更新和细胞存活。