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Published on: February 7, 2018
Redox sensor NPGPx restrains ZAP70 activity and modulates T cell homeostasis
Fang-Yi Su1, Shih-Chia Huang2, Pei-Chi Wei2
1Genomics Research Center, Academia Sinica, Taipei, Taiwan; Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.
Abstract:
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.
Insights
Non-selenium glutathione peroxidase (NPGPx) regulates T cell activation by controlling ZAP70 kinase activity. NPGPx deficiency leads to T cell hyperproliferation and autoimmune responses, highlighting its role in immune homeostasis.
Area of Science:
- Immunology
- Cell Biology
- Redox Biology
Background:
- Reactive oxygen species (ROS) influence T cell signaling.
- ZAP70 is a crucial tyrosine kinase for T cell activation.
- The direct redox regulation of ZAP70 activity remains unclear.
Purpose of the Study:
- To investigate the role of NPGPx in T cell activation and signaling.
- To determine if NPGPx directly modulates ZAP70 activity via redox mechanisms.
- To elucidate the function of NPGPx in maintaining T cell homeostasis.
Main Methods:
- T cell-specific NPGPx-knockout mouse models were generated.
- Proteomic approaches were used to identify NPGPx interacting proteins.
- T cell proliferation, cytokine production, and experimental autoimmune encephalomyelitis (EAE) were assessed.
Main Results:
- NPGPx deficiency caused T cell hyperproliferation and increased cytokine production.
- NPGPx-deficient mice exhibited enhanced T-dependent humoral responses and EAE susceptibility.
- ZAP70 was identified as a key interacting protein of NPGPx via disulfide bonding.
- NPGPx modulates ZAP70 activity through redox switching, reducing its recruitment to the TCR/CD3 complex.
Conclusions:
- NPGPx acts as a redox sensor that regulates ZAP70 activity upon TCR stimulation.
- NPGPx restrains ZAP70 function to maintain T cell homeostasis.
- This study reveals a novel redox mechanism controlling T cell responses.
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