ER-associated degradation in cystinosis pathogenesis and the prospects of precision medicine
Cystinosis is a lysosomal storage disease that is characterized by the accumulation of dipeptide cystine within the lumen. It is caused by mutations in the cystine exporter, cystinosin. Most of the clinically reported mutations are due to the loss of transporter function. In this study, we identifie...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical Investigation
2023-10-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI169551 |
| _version_ | 1797634425377259520 |
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| author | Varsha Venkatarangan Weichao Zhang Xi Yang Jess Thoene Si Houn Hahn Ming Li |
| author_facet | Varsha Venkatarangan Weichao Zhang Xi Yang Jess Thoene Si Houn Hahn Ming Li |
| author_sort | Varsha Venkatarangan |
| collection | DOAJ |
| description | Cystinosis is a lysosomal storage disease that is characterized by the accumulation of dipeptide cystine within the lumen. It is caused by mutations in the cystine exporter, cystinosin. Most of the clinically reported mutations are due to the loss of transporter function. In this study, we identified a rapidly degrading disease variant, referred to as cystinosin(7Δ). We demonstrated that this mutant is retained in the ER and degraded via the ER-associated degradation (ERAD) pathway. Using genetic and chemical inhibition methods, we elucidated the roles of HRD1, p97, EDEMs, and the proteasome complex in cystinosin(7Δ) degradation pathway. Having understood the degradation mechanisms, we tested some chemical chaperones previously used for treating CFTR F508Δ and demonstrated that they could facilitate the folding and trafficking of cystinosin(7Δ). Strikingly, chemical chaperone treatment can reduce the lumenal cystine level by approximately 70%. We believe that our study conclusively establishes the connection between ERAD and cystinosis pathogenesis and demonstrates the possibility of using chemical chaperones to treat cystinosin(7Δ). |
| first_indexed | 2024-03-11T12:07:29Z |
| format | Article |
| id | doaj.art-47e675b8b15a403e9993ece5a0525f9e |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:07:29Z |
| publishDate | 2023-10-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-47e675b8b15a403e9993ece5a0525f9e2023-11-07T16:20:55ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382023-10-0113319ER-associated degradation in cystinosis pathogenesis and the prospects of precision medicineVarsha VenkataranganWeichao ZhangXi YangJess ThoeneSi Houn HahnMing LiCystinosis is a lysosomal storage disease that is characterized by the accumulation of dipeptide cystine within the lumen. It is caused by mutations in the cystine exporter, cystinosin. Most of the clinically reported mutations are due to the loss of transporter function. In this study, we identified a rapidly degrading disease variant, referred to as cystinosin(7Δ). We demonstrated that this mutant is retained in the ER and degraded via the ER-associated degradation (ERAD) pathway. Using genetic and chemical inhibition methods, we elucidated the roles of HRD1, p97, EDEMs, and the proteasome complex in cystinosin(7Δ) degradation pathway. Having understood the degradation mechanisms, we tested some chemical chaperones previously used for treating CFTR F508Δ and demonstrated that they could facilitate the folding and trafficking of cystinosin(7Δ). Strikingly, chemical chaperone treatment can reduce the lumenal cystine level by approximately 70%. We believe that our study conclusively establishes the connection between ERAD and cystinosis pathogenesis and demonstrates the possibility of using chemical chaperones to treat cystinosin(7Δ).https://doi.org/10.1172/JCI169551Cell biologyNephrology |
| spellingShingle | Varsha Venkatarangan Weichao Zhang Xi Yang Jess Thoene Si Houn Hahn Ming Li ER-associated degradation in cystinosis pathogenesis and the prospects of precision medicine The Journal of Clinical Investigation Cell biology Nephrology |
| title | ER-associated degradation in cystinosis pathogenesis and the prospects of precision medicine |
| title_full | ER-associated degradation in cystinosis pathogenesis and the prospects of precision medicine |
| title_fullStr | ER-associated degradation in cystinosis pathogenesis and the prospects of precision medicine |
| title_full_unstemmed | ER-associated degradation in cystinosis pathogenesis and the prospects of precision medicine |
| title_short | ER-associated degradation in cystinosis pathogenesis and the prospects of precision medicine |
| title_sort | er associated degradation in cystinosis pathogenesis and the prospects of precision medicine |
| topic | Cell biology Nephrology |
| url | https://doi.org/10.1172/JCI169551 |
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