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The zinc-finger protein ZFYVE1 modulates TLR3-mediated signaling by facilitating TLR3 ligand binding

Cellular & Molecular Immunology volume 17, pages 741–752 (2020)Cite this article

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Abstract

Recognition of viral dsRNA by Toll-like receptor 3 (TLR3) leads to the induction of downstream antiviral effectors and the innate antiviral immune response. Here, we identified the zinc-finger FYVE domain-containing protein ZFYVE1, a guanylate-binding protein (GBP), as a positive regulator of TLR3-mediated signaling. Overexpression of ZFYVE1 promoted the transcription of downstream antiviral genes upon stimulation with the synthetic TLR3 ligand poly(I:C). Conversely, ZFYVE1 deficiency had the opposite effect. Zfyve1−/− mice were less susceptible than wild-type mice to inflammatory death induced by poly(I:C) but not LPS. ZFYVE1 was associated with TLR3, and the FYVE domain of ZFYVE1 and the ectodomain of TLR3 were shown to be responsible for their interaction. ZFYVE1 was bound to poly(I:C) and increased the binding affinity of TLR3 to poly(I:C). These findings suggest that ZFYVE1 plays an important role in the TLR3-mediated innate immune and inflammatory responses by promoting the ligand binding of TLR3.

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Acknowledgements

This work was supported by grants from the State Key R&D Program of China (2017YFA0505800, 2016YFA0502102 and 2018YFA0800700), the National Natural Science Foundation of China (31830024, 31630045, 31870870, 31800728, 31771555, and 31671418), the China Postdoctoral Science Foundation (2017M620334), the Fundamental Research Funds for the Central Universities (2042019kf0204), and the Natural Science Foundation of Hubei Province (2018CFA016).

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Authors and Affiliations

  1. College of Life Sciences, Wuhan University, Wuhan, 430072, China

    Xuan Zhong, Lu Feng, Wen-Hua Xu, Xin Wu, Yi-Di Ding, Yan Zhou, Cao-Qi Lei & Hong-Bing Shu

  2. Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430072, China

    Xuan Zhong, Lu Feng, Wen-Hua Xu, Xin Wu, Yan Zhou, Cao-Qi Lei & Hong-Bing Shu

  3. Medical Research Institute, Wuhan University, Wuhan, 430072, China

    Xuan Zhong, Lu Feng, Wen-Hua Xu, Xin Wu, Yan Zhou, Cao-Qi Lei & Hong-Bing Shu

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  1. Xuan Zhong
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  2. Lu Feng
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Contributions

H.-B.S. and X.Z. designed the study; X.Z., L.F., W.-H.X., X.W., and Y.-D.D. performed the experiments; H.-B.S., C.-Q.L., Y.Z., and X.Z. analyzed the data; and H.-B.S., C.-Q.L., and X.Z. wrote the paper.

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Correspondence to Cao-Qi Lei or Hong-Bing Shu.

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Zhong, X., Feng, L., Xu, WH. et al. The zinc-finger protein ZFYVE1 modulates TLR3-mediated signaling by facilitating TLR3 ligand binding. Cell Mol Immunol 17, 741–752 (2020). https://doi.org/10.1038/s41423-019-0265-6

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