Lysosomal cystine export regulates mTORC1 signaling to guide kidney epithelial cell fate specialization
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 ly...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-39261-3 |
| _version_ | 1797778744808570880 |
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| author | Marine Berquez Zhiyong Chen Beatrice Paola Festa Patrick Krohn Svenja Aline Keller Silvia Parolo Mikhail Korzinkin Anna Gaponova Endre Laczko Enrico Domenici Olivier Devuyst Alessandro Luciani |
| author_facet | Marine Berquez Zhiyong Chen Beatrice Paola Festa Patrick Krohn Svenja Aline Keller Silvia Parolo Mikhail Korzinkin Anna Gaponova Endre Laczko Enrico Domenici Olivier Devuyst Alessandro Luciani |
| author_sort | Marine Berquez |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T23:21:57Z |
| format | Article |
| id | doaj.art-11a5f48d3b2345418cf8893bc3e0feb9 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-12T23:21:57Z |
| publishDate | 2023-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-11a5f48d3b2345418cf8893bc3e0feb92023-07-16T11:21:48ZengNature PortfolioNature Communications2041-17232023-07-0114112110.1038/s41467-023-39261-3Lysosomal cystine export regulates mTORC1 signaling to guide kidney epithelial cell fate specializationMarine Berquez0Zhiyong Chen1Beatrice Paola Festa2Patrick Krohn3Svenja Aline Keller4Silvia Parolo5Mikhail Korzinkin6Anna Gaponova7Endre Laczko8Enrico Domenici9Olivier Devuyst10Alessandro Luciani11Institute of Physiology, University of ZurichInstitute of Physiology, University of ZurichInstitute of Physiology, University of ZurichInstitute of Physiology, University of ZurichInstitute of Physiology, University of ZurichFondazione The Microsoft Research University of Trento—Centre for Computational and Systems Biology (COSBI)Insilico Medicine Hong Kong Ltd., Hong Kong Science and Technology Park, Hong KongInsilico Medicine Hong Kong Ltd., Hong Kong Science and Technology Park, Hong KongFunctional Genomics Center Zurich, University of ZurichFondazione The Microsoft Research University of Trento—Centre for Computational and Systems Biology (COSBI)Institute of Physiology, University of ZurichInstitute of Physiology, University of ZurichAbstract 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.https://doi.org/10.1038/s41467-023-39261-3 |
| spellingShingle | Marine Berquez Zhiyong Chen Beatrice Paola Festa Patrick Krohn Svenja Aline Keller Silvia Parolo Mikhail Korzinkin Anna Gaponova Endre Laczko Enrico Domenici Olivier Devuyst Alessandro Luciani Lysosomal cystine export regulates mTORC1 signaling to guide kidney epithelial cell fate specialization Nature Communications |
| title | Lysosomal cystine export regulates mTORC1 signaling to guide kidney epithelial cell fate specialization |
| title_full | Lysosomal cystine export regulates mTORC1 signaling to guide kidney epithelial cell fate specialization |
| title_fullStr | Lysosomal cystine export regulates mTORC1 signaling to guide kidney epithelial cell fate specialization |
| title_full_unstemmed | Lysosomal cystine export regulates mTORC1 signaling to guide kidney epithelial cell fate specialization |
| title_short | Lysosomal cystine export regulates mTORC1 signaling to guide kidney epithelial cell fate specialization |
| title_sort | lysosomal cystine export regulates mtorc1 signaling to guide kidney epithelial cell fate specialization |
| url | https://doi.org/10.1038/s41467-023-39261-3 |
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