Lysosomal cystine export regulates mTORC1 signaling to guide kidney epithelial cell fate specialization

Marine Berquez, Zhiyong Chen, Beatrice Paola Festa, Patrick Krohn, Svenja Aline Keller, Silvia Parolo, Mikhail Korzinkin, Anna Gaponova, Endre Laczko, Enrico Domenici, Olivier Devuyst () and Alessandro Luciani ()
Additional contact information
Marine Berquez: University of Zurich
Zhiyong Chen: University of Zurich
Beatrice Paola Festa: University of Zurich
Patrick Krohn: University of Zurich
Svenja Aline Keller: University of Zurich
Silvia Parolo: Fondazione The Microsoft Research University of Trento—Centre for Computational and Systems Biology (COSBI)
Mikhail Korzinkin: Insilico Medicine Hong Kong Ltd., Hong Kong Science and Technology Park, Hong Kong
Anna Gaponova: Insilico Medicine Hong Kong Ltd., Hong Kong Science and Technology Park, Hong Kong
Endre Laczko: University of Zurich
Enrico Domenici: Fondazione The Microsoft Research University of Trento—Centre for Computational and Systems Biology (COSBI)
Olivier Devuyst: University of Zurich
Alessandro Luciani: University of Zurich

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-39261-3

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