ATM phosphorylation of CD98HC increases antiporter membrane localization and prevents chronic toxic glutamate accumulation in Ataxia telangiectasia.
| Title: | ATM phosphorylation of CD98HC increases antiporter membrane localization and prevents chronic toxic glutamate accumulation in Ataxia telangiectasia. |
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| Authors: | Bishop A; University of Texas Health at San Antonio.; Romero JC; University of Texas Health at San Antonio.; Tonapi S; University of Texas Health at San Antonio.; Parihar M; University of Texas Health at San Antonio.; Loranc E; University of Texas Health at San Antonio.; Miller H; University of Texas Health at San Antonio.; Lawrence L; University of Texas Health at San Antonio.; Bassani N; University of Texas Health at San Antonio.; Robledo D; University of Texas Health at San Antonio.; Cao L; University of Texas Health at San Antonio.; Nie J; University of Texas Health at San Antonio.; Kanda K; University of Texas Health at San Antonio.; Stoja A; University of Texas Health at San Antonio.; Garcia N; University of Texas Health at San Antonio.; Gorthi A; University of Texas Health at San Antonio.; Stoveken B; University of Texas Health at San Antonio.; Lane A; University of Kentucky College of Medicine.; Fan T; Center for Environmental and Systems Biochemistry, University of Kentucky.; Cassel T; Markey Cancer Center, University of Kentucky.; Zha S; Columbia University.; Musi N; University of California. |
| Source: | Research square [Res Sq] 2024 Sep 05. Date of Electronic Publication: 2024 Sep 05. |
| Publication Type: | Journal Article; Preprint |
| Language: | English |
| Journal Info: | Country of Publication: United States NLM ID: 101768035 Publication Model: Electronic Cited Medium: Internet ISSN: 2693-5015 (Electronic) Linking ISSN: 26935015 NLM ISO Abbreviation: Res Sq Subsets: PubMed not MEDLINE |
| Abstract: | Ataxia telangiectasia (A-T) is a rare genetic disorder characterized by neurological defects, immunodeficiency, cancer predisposition, radiosensitivity, decreased blood vessel integrity, and diabetes. ATM, the protein mutated in A-T, responds to DNA damage and oxidative stress, but its functional relationship to the progressive clinical manifestation of A-T is not understood. CD98HC chaperones cystine/glutamate (xc -L) 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 SLC family antiporters relevant to A-T 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 both in ATM-deficient cells and mouse models. These findings provide new insight into the long-known benefits of N-acetyl cysteine to A-T cells beyond oxidative stress through removing excess glutamate by production of glutathione.+L) 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 SLC family antiporters relevant to A-T 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 both in ATM-deficient cells and mouse models. These findings provide new insight into the long-known benefits of N-acetyl cysteine to A-T cells beyond oxidative stress through removing excess glutamate by production of glutathione. |
| Competing Interests: | Declaration of interest The authors declare no competing financial interests. |
| Comments: | Update in: Nat Commun. 2025 Jun 2;16(1):5109. doi: 10.1038/s41467-025-60304-4.. (PMID: 40456742) |
| Grant Information: | T32 AG021890 United States AG NIA NIH HHS; R01 CA241554 United States CA NCI NIH HHS; F31 AG072902 United States AG NIA NIH HHS; TL1 TR002647 United States TR NCATS NIH HHS; P30 CA054174 United States CA NCI NIH HHS; K22 ES012264 United States ES NIEHS NIH HHS; P30 CA177558 United States CA NCI NIH HHS; T32 CA148724 United States CA NCI NIH HHS |
| Entry Date(s): | Date Created: 20240916 Latest Revision: 20250610 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC11398575 |
| DOI: | 10.21203/rs.3.rs-4947457/v1 |
| PMID: | 39281865 |
| Database: | MEDLINE |
Journal Article; Preprint