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

Redox sensor NPGPx restrains ZAP70 activity and modulates T cell homeostasis.
Free Radic Biol Med. 2021 Jan 15;:
Authors: Su FY, Huang SC, Wei PC, Hsu PH, Li JP, Su LW, Hsieh YL, Hu CM, Hsu JL, Yang CY, Chung CY, Shew JY, Lan JL, Sytwu HK, Y-Hp Lee E, Lee WH
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.
PMID: 33460768 [PubMed - as ...

Source: Free Radical Biology and Medicine - January 15, 2021 Category: Biology Authors: Su FY, Huang SC, Wei PC, Hsu PH, Li JP, Su LW, Hsieh YL, Hu CM, Hsu JL, Yang CY, Chung CY, Shew JY, Lan JL, Sytwu HK, Y-Hp Lee E, Lee WH Tags: Free Radic Biol Med Source Type: research