Loss of CD98HC phosphorylation by ATM impairs antiporter trafficking and drives glutamate toxicity in Ataxia telangiectasia
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.
Authors
- Brian Stoveken (ORCID: https://orcid.org/0000-0002-9186-6154)
- Henry E. Miller (ORCID: https://orcid.org/0000-0003-3756-3918)
- Alexander J.R. Bishop (ORCID: https://orcid.org/0000-0002-5742-4387)
- Andrew N. Lane (ORCID: https://orcid.org/0000-0003-1121-5106)
- Nicolas Musi (ORCID: https://orcid.org/0000-0003-4242-2888)
- Shan Zha (ORCID: https://orcid.org/0000-0002-6568-1818)
- James D. Lechleiter (ORCID: https://orcid.org/0000-0001-9000-0722)
- Lily Dong (ORCID: https://orcid.org/0000-0002-6293-818X)
- Aiola Stoja (ORCID: https://orcid.org/0000-0002-8288-000X)
- Liesl A. Lawrence (ORCID: https://orcid.org/0000-0001-8809-6278)
- Jia Nie (ORCID: https://orcid.org/0000-0001-9085-7224)
- Eva Loranc
- July Carolina Romero (ORCID: https://orcid.org/0000-0003-4845-5752)
- Teresa W.‐M. Fan (ORCID: https://orcid.org/0000-0002-7292-8938)
- Aparna Gorthi (ORCID: https://orcid.org/0000-0001-5935-4098)
- Natália Garcia (ORCID: https://orcid.org/0000-0002-7472-2650)
- Sonal S. Tonapi
- Nicklas Bassani (ORCID: https://orcid.org/0000-0001-9407-7348)
- Teresa Cassel (ORCID: https://orcid.org/0000-0003-1700-932X)
- Lin Cao (ORCID: https://orcid.org/0000-0001-5355-8751)
- Manish Parihar (ORCID: https://orcid.org/0000-0003-3258-5472)
- Kairi Kanda
- Daniel G Robledo
Institutions
- Universidad Mayor de San Andrés (BO)
- Cedars-Sinai Medical Center (US)
- Nationwide Children's Hospital (US)
- The University of Texas at San Antonio Health Science Center (US)
- Markey Cancer Center (US)
- Longevity Biotech (United States) (US)
- Cancer Research Institute of the Slovak Academy of Sciences (SK)
- Cancer Genetics (United States) (US)
- Mays Cancer Center at UT Health San Antonio (US)
- Columbia University (US)
- The University of Texas Health Science Center at Houston (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-06-02
- DOI
- https://doi.org/10.1038/s41467-025-60304-4
- Citations
- 2
- Primary Topic
- DNA Repair Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- AstraZeneca
- Cancer Prevention and Research Institute of Texas
- Max and Minnie Tomerlin Voelcker Fund
- Cancer Research UK
- National Institutes of Health