# ATM phosphorylation of CD98HC increases antiporter membrane localization and prevents chronic toxic glutamate accumulation in Ataxia telangiectasia

## TL;DR

This paper shows how ATM protein helps prevent toxic glutamate buildup in Ataxia telangiectasia by regulating CD98HC and amino acid transporters.

## Contribution

The study reveals a novel role of ATM phosphorylation in preventing glutamate accumulation through CD98HC and antiporter regulation in Ataxia telangiectasia.

## Key findings

- ATM phosphorylation of CD98HC increases antiporter membrane localization.
- Loss of ATM leads to toxic glutamate accumulation in ATM-deficient cells and mouse models.
- Bypassing antiporters restores metabolic balance in ATM-deficient cells.

## 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−) and cationic/neutral amino acid (y+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.