Differentiation is critical for cell fate decisions, but the signals involved remain unclear. The kidney proximal tubule (PT) cells reabsorb disulphide-rich proteins through endocytosis, generating cystine via lysosomal proteolysis. Here we report that defective cystine mobilization from lysosomes through cystinosin (CTNS), which is mutated in cystinosis, diverts PT cells towards growth and proliferation, disrupting their functions. Mechanistically, cystine storage stimulates Ragulator-Rag GTPase-dependent recruitment of mechanistic target of rapamycin complex 1 (mTORC1) and its constitutive activation. Re-introduction of CTNS restores nutrient-dependent regulation of mTORC1 in knockout cells, whereas cell-permeant analogues of L-cystine, accumulating within lysosomes, render wild-type cells resistant to nutrient withdrawal. Therapeutic mTORC1 inhibition corrects lysosome and differentiation downstream of cystine storage, and phenotypes in preclinical models of cystinosis. Thus, cystine serves as a lysosomal signal that tailors mTORC1 and metabolism to direct epithelial cell fate decisions. These results identify mechanisms and therapeutic targets for dysregulated homeostasis in cystinosis.

分化对于细胞命运的决定至关重要，但所涉及的信号仍不清楚。肾近端小管（PT）细胞通过内吞作用重吸收富含二硫键的蛋白质，通过溶酶体蛋白水解产生胱氨酸。在这里，我们报道了通过胱氨酸蛋白酶（CTNS）从溶酶体动员缺陷的胱氨酸，这种蛋白质在胱氨酸病中发生突变，使 PT 细胞转向生长和增殖，破坏其功能。从机制上讲，胱氨酸储存刺激 Ragulator-Rag GTPase 依赖性招募雷帕霉素复合物 1 (mTORC1) 的机制靶点及其组成型激活。重新引入 CTNS 可恢复敲除细胞中 mTORC1 的营养依赖性调节，而细胞渗透的 L-胱氨酸类似物在溶酶体中积累，使野生型细胞对营养撤退具有抵抗力。治疗性 mTORC1 抑制可纠正胱氨酸储存下游的溶酶体和分化，以及胱氨酸病临床前模型的表型。因此，胱氨酸充当溶酶体信号，调整 mTORC1 和代谢以指导上皮细胞的命运决定。这些结果确定了胱氨酸中毒体内平衡失调的机制和治疗靶点。