Redox sensor NPGPx restrains ZAP70 activity and modulates T cell homeostasis.

Emerging evidences implicate the contribution of ROS to T cell activation and signaling. The tyrosine kinase, ζ-chain-associated protein of 70 kDa (ZAP70), is essential for T cell development and activation. However, it remains elusive whether a direct redox regulation affects ZAP70 activity upon TCR stimulation. Here, we show that deficiency of non-selenocysteine containing phospholipid hydroperoxide glutathione peroxidase (NPGPx), a redox sensor, results in T cell hyperproliferation and elevated cytokine productions. T cell-specific NPGPx-knockout mice reveal enhanced T-dependent humoral responses and are susceptible to experimental autoimmune encephalomyelitis (EAE). Through proteomic approaches, ZAP70 is identified as the key interacting protein of NPGPx through disulfide bonding. NPGPx is activated by ROS generated from TCR stimulation, and modulates ZAP70 activity through redox switching to reduce ZAP70 recruitment to TCR/CD3 complex in membrane lipid raft, therefore subduing TCR responses. These results reveal a delicate redox mechanism that NPGPx serves as a modulator to curb ZAP70 functions in maintaining T cell homeostasis. Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Fang-Yi Su, Shih-Chia Huang, Pei-Chi Wei, Pang-Hung Hsu, Ju-Pi Li, Li-Wen Su, Yung-Lin Hsieh, Chun-Mei Hu, Jye-Lin Hsu, Cheng-Yuan Yang, Chen-Yen Chung, Jin-Yuh Shew, Joung-Liang Lan, Huey-Kang Sytwu, Eva Y-Hp Lee, Wen-Hwa Lee. Redox sensor NPGPx restrains ZAP70 activity and modulates T cell homeostasis. Free radical biology & medicine. 2021 Mar;165:368-384

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PMID: 33460768

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