Loss of CD98HC phosphorylation by ATM impairs antiporter trafficking and drives glutamate toxicity in Ataxia telangiectasia
Abstract Ataxia-telangiectasia is a rare genetic disorder characterized by neurological defects, immunodeficiency, cancer predisposition, radiosensitivity, decreased blood vessel integrity, and diabetes. ATM, the protein mutated in Ataxia-telangiectasia, responds to DNA damage and oxidative stress,...
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Nature Portfolio
2025-06-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60304-4 |
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| author | July Carolina Romero Sonal S. Tonapi Manish Parihar Eva Loranc Henry E. Miller Liesl A. Lawrence Nicklas Bassani Daniel G. Robledo Lin Cao Jia Nie Kairi Kanda Aiola Stoja Natalia Garcia Aparna Gorthi Brian J. Stoveken Teresa W-M Fan Teresa A. Cassel Shan Zha James D. Lechleiter Nicolas Musi Lily Q. Dong Andrew N. Lane Alexander J. R. Bishop |
| author_facet | July Carolina Romero Sonal S. Tonapi Manish Parihar Eva Loranc Henry E. Miller Liesl A. Lawrence Nicklas Bassani Daniel G. Robledo Lin Cao Jia Nie Kairi Kanda Aiola Stoja Natalia Garcia Aparna Gorthi Brian J. Stoveken Teresa W-M Fan Teresa A. Cassel Shan Zha James D. Lechleiter Nicolas Musi Lily Q. Dong Andrew N. Lane Alexander J. R. Bishop |
| author_sort | July Carolina Romero |
| collection | DOAJ |
| description | Abstract Ataxia-telangiectasia is a rare genetic disorder characterized by neurological defects, immunodeficiency, cancer predisposition, radiosensitivity, decreased blood vessel integrity, and diabetes. ATM, the protein mutated in Ataxia-telangiectasia, responds to DNA damage and oxidative stress, but its functional relationship to the progressive clinical manifestation of this disorder is not understood. CD98HC chaperones cystine/glutamate and cationic/neutral amino acid antiporters to the cell membrane, and CD98HC phosphorylation by ATM accelerates membrane localization to acutely increase amino acid transport. Loss of ATM impacts tissues reliant on heterodimeric amino acid transporters relevant to Ataxia-telangiectasia phenotypes, such as endothelial cells (telangiectasia) and pancreatic α-cells (fatty liver and diabetes), with toxic glutamate accumulation. Bypassing the antiporters restores intracellular metabolic balance in ATM-deficient cells and mouse models. These findings provide insight into the long-known benefits of N-acetyl cysteine in Ataxia-telangiectasia cells beyond oxidative stress through removing glutamate excess by producing glutathione. |
| format | Article |
| id | doaj-art-d3673f3b29a8450eb8c2a45a0a22de22 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-d3673f3b29a8450eb8c2a45a0a22de222025-08-20T03:26:43ZengNature PortfolioNature Communications2041-17232025-06-0116112110.1038/s41467-025-60304-4Loss of CD98HC phosphorylation by ATM impairs antiporter trafficking and drives glutamate toxicity in Ataxia telangiectasiaJuly Carolina Romero0Sonal S. Tonapi1Manish Parihar2Eva Loranc3Henry E. Miller4Liesl A. Lawrence5Nicklas Bassani6Daniel G. Robledo7Lin Cao8Jia Nie9Kairi Kanda10Aiola Stoja11Natalia Garcia12Aparna Gorthi13Brian J. Stoveken14Teresa W-M Fan15Teresa A. Cassel16Shan Zha17James D. Lechleiter18Nicolas Musi19Lily Q. Dong20Andrew N. Lane21Alexander J. R. Bishop22Cell Systems and Anatomy, UT Health San AntonioCell Systems and Anatomy, UT Health San AntonioCell Systems and Anatomy, UT Health San AntonioGreehey Children’s Cancer Research Institute, UT Health San AntonioGreehey Children’s Cancer Research Institute, UT Health San AntonioCell Systems and Anatomy, UT Health San AntonioCell Systems and Anatomy, UT Health San AntonioGreehey Children’s Cancer Research Institute, UT Health San AntonioGreehey Children’s Cancer Research Institute, UT Health San AntonioBarshop Institute for Longevity and Aging Studies, Health San AntonioCell Systems and Anatomy, UT Health San AntonioCell Systems and Anatomy, UT Health San AntonioCell Systems and Anatomy, UT Health San AntonioCell Systems and Anatomy, UT Health San AntonioCell Systems and Anatomy, UT Health San AntonioToxicology and Cancer Biology, Markey Cancer Center, University of KentuckyToxicology and Cancer Biology, Markey Cancer Center, University of KentuckyInstitute for Cancer Genetics, Vagelos College of Physicians and Surgeons, Columbia UniversityCell Systems and Anatomy, UT Health San AntonioBarshop Institute for Longevity and Aging Studies, Health San AntonioCell Systems and Anatomy, UT Health San AntonioToxicology and Cancer Biology, Markey Cancer Center, University of KentuckyCell Systems and Anatomy, UT Health San AntonioAbstract Ataxia-telangiectasia is a rare genetic disorder characterized by neurological defects, immunodeficiency, cancer predisposition, radiosensitivity, decreased blood vessel integrity, and diabetes. ATM, the protein mutated in Ataxia-telangiectasia, responds to DNA damage and oxidative stress, but its functional relationship to the progressive clinical manifestation of this disorder is not understood. CD98HC chaperones cystine/glutamate and cationic/neutral amino acid antiporters to the cell membrane, and CD98HC phosphorylation by ATM accelerates membrane localization to acutely increase amino acid transport. Loss of ATM impacts tissues reliant on heterodimeric amino acid transporters relevant to Ataxia-telangiectasia phenotypes, such as endothelial cells (telangiectasia) and pancreatic α-cells (fatty liver and diabetes), with toxic glutamate accumulation. Bypassing the antiporters restores intracellular metabolic balance in ATM-deficient cells and mouse models. These findings provide insight into the long-known benefits of N-acetyl cysteine in Ataxia-telangiectasia cells beyond oxidative stress through removing glutamate excess by producing glutathione.https://doi.org/10.1038/s41467-025-60304-4 |
| spellingShingle | July Carolina Romero Sonal S. Tonapi Manish Parihar Eva Loranc Henry E. Miller Liesl A. Lawrence Nicklas Bassani Daniel G. Robledo Lin Cao Jia Nie Kairi Kanda Aiola Stoja Natalia Garcia Aparna Gorthi Brian J. Stoveken Teresa W-M Fan Teresa A. Cassel Shan Zha James D. Lechleiter Nicolas Musi Lily Q. Dong Andrew N. Lane Alexander J. R. Bishop Loss of CD98HC phosphorylation by ATM impairs antiporter trafficking and drives glutamate toxicity in Ataxia telangiectasia Nature Communications |
| title | Loss of CD98HC phosphorylation by ATM impairs antiporter trafficking and drives glutamate toxicity in Ataxia telangiectasia |
| title_full | Loss of CD98HC phosphorylation by ATM impairs antiporter trafficking and drives glutamate toxicity in Ataxia telangiectasia |
| title_fullStr | Loss of CD98HC phosphorylation by ATM impairs antiporter trafficking and drives glutamate toxicity in Ataxia telangiectasia |
| title_full_unstemmed | Loss of CD98HC phosphorylation by ATM impairs antiporter trafficking and drives glutamate toxicity in Ataxia telangiectasia |
| title_short | Loss of CD98HC phosphorylation by ATM impairs antiporter trafficking and drives glutamate toxicity in Ataxia telangiectasia |
| title_sort | loss of cd98hc phosphorylation by atm impairs antiporter trafficking and drives glutamate toxicity in ataxia telangiectasia |
| url | https://doi.org/10.1038/s41467-025-60304-4 |
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