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Wdfy1 deficiency impairs Tlr3-mediated immune responses in vivo

Cellular & Molecular Immunology volume 17, pages 1014–1016 (2020)Cite this article

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As germline-encoded pattern recognition receptors, Toll-like receptors (TLRs) play important roles in innate immune responses against various pathogens.1 Among TLR family members, only TLR3 and TLR4 use TIR domain-containing adapter-inducing interferon-β (TRIF) as an adapter protein to trigger the production of type I interferon (IFN-Ι) and inflammatory cytokines.1,2 Secreted IFNs then bind their plasma membrane receptors, further stimulating the transcription of IFN-stimulated genes (ISGs), which have multiple antiviral functions, such as restricting the replication and assembly of viral particles.3 We previously reported an accessory protein, named WD repeat and FYVE domain-containing protein (WDFY1), that strengths the interaction between TRIF and TLR3 or TLR4.4 At the cellular level, overexpression of WDFY1 reinforced TLR3/4-mediated innate immune responses, and the suppression of WDFY1 by RNAi had the opposite effects. We also reported that the function of WDFY1 is highly dependent on its FYVE domain, which is responsible for its localization to the early endosome.5 However, whether Wdfy1-knockout (KO) mice are susceptible to Tlr3 or Tlr4 ligands remains unknown.

We then performed similar experiments using mouse embryonic fibroblasts (MEFs). Knockout of Wdfy1 markedly impaired poly I:C-induced transcription of Ifnb1, Isg56, Tnfa, Il6, and Il1b (Fig. 1b). However, in LPS-treated MEFs, knockout of Wdfy1 impaired the transcription of Ifnb1 but had no marked effect on the transcription of Isg56, Tnfa, Il6, or Il1b (Supplementary information, Fig. S1b). These results suggest that in nonimmune cells, Wdfy1 mainly participates in Tlr3 signaling and Tlr4-mediated production of Ifn-I but not Tlr4-mediated production of inflammatory cytokines.

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Fig. 1: Wdfy1 deficiency impaired Tlr3-mediated immune responses in vivo.

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Acknowledgements

This work was supported by the National Key Research and Development Program of China (2018YFA0800700) and the National Natural Science Foundation of China (31970894, 31770941).

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Authors and Affiliations

  1. State Key Laboratory of Virology, Frontier Science Center for Immunology and Metabolism, College of Life Sciences, Wuhan University, Wuhan, 430072, China

    Yang Yang & Yu Liu

  2. State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Sciences, Hubei University, Wuhan, 430062, China

    Yun-Hong Hu

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  1. Yang Yang
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Y.Y. and Y.H.H. performed the experiments and analyzed the data, L.Y. designed the research and wrote the paper.

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Correspondence to Yu Liu.

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Yang, Y., Hu, YH. & Liu, Y. Wdfy1 deficiency impairs Tlr3-mediated immune responses in vivo. Cell Mol Immunol 17, 1014–1016 (2020). https://doi.org/10.1038/s41423-020-0461-4

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