Loss of CD98HC phosphorylation by ATM impairs antiporter trafficking and drives glutamate toxicity in Ataxia telangiectasia

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

doi:10.1038/s41467-025-60304-4

Loss of CD98HC phosphorylation by ATM impairs antiporter trafficking and drives glutamate toxicity in Ataxia telangiectasia

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

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

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.

Original language	English
Article number	5109
Journal	Nature Communications
Volume	16
Issue number	1
DOIs	https://doi.org/10.1038/s41467-025-60304-4
State	Published - Dec 2025

Bibliographical note

Publisher Copyright:
© The Author(s) 2025.

Funding

We are grateful to the UTH-SA/Cancer Center Sequencing core. Human tissue was obtained from the NIH NeuroBioBank at the University of Maryland, USA. NMR and MS were recorded using the Metabolism Shared Resources supported in part by P30CA177558 (to B.M.E.). This work was funded by the NIH (K22ES012264, R01CA152063 R01CA241554), a Voelcker Fund Young Investigator Award, CPRIT (RP150445), Stand Up 2 Cancer-Cancer Research UK (RT6187) and GCCRI pilot funds to A.J.R.B.; CPRIT (RP140105) to J.C.R.; NIH T32 (5T32CA148724-3) to S.S.T; NIH T32 (AG021890) to J.N.; DoD grant (W81XWH-19-1-0180) and TL1 (TL1TR002647) to L.A.L.; 2018 AACR-AstraZeneca START grant (18-40-12-GORT) to A.G.; Greehey Family Foundation and NIH (F31AG072902) to H.E.M.; Greehey Family Foundation and GSBS-T32 (CA291696) to A.S.; MCC-T32 (CA148724) to K.K.; and NIH (P30CA054174) to MCC support sequencing core.

Funders	Funder number
Greehey Family Foundation	P30CA054174, CA291696, MCC-T32, CA148724, F31AG072902, GSBS-T32
Cancer Prevention and Research Institute of Texas	RP150445
Yorkshire Cancer Research/Cancer Research UK Sheffield Cancer Centre	RT6187
U.S. Department of Defense	TL1TR002647, W81XWH-19-1-0180, 18-40-12-GORT
GCCRI	AG021890, RP140105, 5T32CA148724-3
National Institutes of Health (NIH)	R01CA152063 R01CA241554, K22ES012264

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General
General Physics and Astronomy

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10.1038/s41467-025-60304-4

Cite this

Romero, J. C., Tonapi, S. S., Parihar, M., Loranc, E., Miller, H. E., Lawrence, L. A., Bassani, N., Robledo, D. G., Cao, L., Nie, J., Kanda, K., Stoja, A., Garcia, N., Gorthi, A., Stoveken, B. J., Fan, T. W. M., Cassel, T. A., Zha, S., Lechleiter, J. D., ... Bishop, A. J. R. (2025). Loss of CD98HC phosphorylation by ATM impairs antiporter trafficking and drives glutamate toxicity in Ataxia telangiectasia. Nature Communications, 16(1), Article 5109. https://doi.org/10.1038/s41467-025-60304-4

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title = "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, 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.",

author = "Romero, \{July Carolina\} and Tonapi, \{Sonal S.\} and Manish Parihar and Eva Loranc and Miller, \{Henry E.\} and Lawrence, \{Liesl A.\} and Nicklas Bassani and Robledo, \{Daniel G.\} and Lin Cao and Jia Nie and Kairi Kanda and Aiola Stoja and Natalia Garcia and Aparna Gorthi and Stoveken, \{Brian J.\} and Fan, \{Teresa W.M.\} and Cassel, \{Teresa A.\} and Shan Zha and Lechleiter, \{James D.\} and Nicolas Musi and Dong, \{Lily Q.\} and Lane, \{Andrew N.\} and Bishop, \{Alexander J.R.\}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = dec,

doi = "10.1038/s41467-025-60304-4",

language = "English",

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Romero, JC, Tonapi, SS, Parihar, M, Loranc, E, Miller, HE, Lawrence, LA, Bassani, N, Robledo, DG, Cao, L, Nie, J, Kanda, K, Stoja, A, Garcia, N, Gorthi, A, Stoveken, BJ, Fan, TWM, Cassel, TA, Zha, S, Lechleiter, JD, Musi, N, Dong, LQ, Lane, AN & Bishop, AJR 2025, 'Loss of CD98HC phosphorylation by ATM impairs antiporter trafficking and drives glutamate toxicity in Ataxia telangiectasia', Nature Communications, vol. 16, no. 1, 5109. https://doi.org/10.1038/s41467-025-60304-4

TY - JOUR

T1 - Loss of CD98HC phosphorylation by ATM impairs antiporter trafficking and drives glutamate toxicity in Ataxia telangiectasia

AU - Romero, July Carolina

AU - Tonapi, Sonal S.

AU - Parihar, Manish

AU - Loranc, Eva

AU - Miller, Henry E.

AU - Lawrence, Liesl A.

AU - Bassani, Nicklas

AU - Robledo, Daniel G.

AU - Cao, Lin

AU - Nie, Jia

AU - Kanda, Kairi

AU - Stoja, Aiola

AU - Garcia, Natalia

AU - Gorthi, Aparna

AU - Stoveken, Brian J.

AU - Fan, Teresa W.M.

AU - Cassel, Teresa A.

AU - Zha, Shan

AU - Lechleiter, James D.

AU - Musi, Nicolas

AU - Dong, Lily Q.

AU - Lane, Andrew N.

AU - Bishop, Alexander J.R.

PY - 2025/12

Y1 - 2025/12

N2 - 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.

AB - 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.

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U2 - 10.1038/s41467-025-60304-4

DO - 10.1038/s41467-025-60304-4

M3 - Article

C2 - 40456742

AN - SCOPUS:105007101063

SN - 2041-1723

VL - 16

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 5109

ER -

Loss of CD98HC phosphorylation by ATM impairs antiporter trafficking and drives glutamate toxicity in Ataxia telangiectasia

Abstract

Bibliographical note

Funding

UN SDGs

ASJC Scopus subject areas

Access to Document

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