IRF3 Negatively Regulates Toll-Like Receptor-Mediated NF-κB Signaling by Targeting TRIF for Degradation in Teleost Fish

Frontiers in Immunology
Xueyan ZhaoTianjun Xu

Abstract

NF-κB signaling is tightly regulated and essential to innate and adaptive immune responses, its regulatory mechanism remains unclear in various organisms, especially teleosts. In this study, we reported that IRF3 can negatively regulate TRIF-mediated NF-κB signaling pathway. Overexpression of IRF3 can inhibit TRIF-mediated NF-κB signaling pathway. However, knockdown of IRF3 had an opposite effect. IRF3 can promote the degradation of TRIF protein in mammal and fish cells, but this effect could be inhibited by MG132 treatment. Furthermore, we found that the inhibitory effect of IRF3 primary depended on its IRF association domain domain. IRF3 is crucial for the polyubiquitination and proteasomal degradation of TRIF. Our findings indicate that IRF3 negatively regulates TLR-mediated NF-κB signaling pathway by targeting TRIF for ubiquitination and degradation. This study provides a novel evidence on the negative regulation of innate immune signaling pathways in teleost fish and thus might provide new insights into the regulatory mechanisms in mammals.

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Citations

Dec 1, 2019·Journal of Clinical Laboratory Analysis·Zuolin YingChuang Gao
Mar 1, 2020·The Journal of Immunology : Official Journal of the American Association of Immunologists·Zhuang WangDahai Yang
May 7, 2020·Frontiers in Immunology·Xiaolong YanTianjun Xu
Jan 3, 2021·Developmental and Comparative Immunology·Nguyen Bao TrungPo-Tsang Lee
Nov 17, 2020·Drug Design, Development and Therapy·Rui GuoGuanwei Fan
Mar 31, 2021·Acta Biochimica Et Biophysica Sinica·Jiangwen DaiZhongjun Wu

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Methods Mentioned

BETA
ubiquitination
PCR
immunoprecipitation
fluorescence microscopy
transfection
co-immunoprecipitation

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