Grass carp (Ctenopharyngodon idellus) TRAF6 up-regulates IFN1 expression by activating IRF5

Li, Yinping; Mao, Yuexin; Yu, Ningli; Xu, Xiaowen; Li, Meifeng; Jiang, Zeyin; Wu, Chuxin; Xu, Kang; Chang, Kaile; Wang, Shanghong; Mao, Huiling; Hu, Chengyu

doi:10.1016/j.dci.2019.103475

Cited by 12 publications

(3 citation statements)

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“…Our work veri ed that IRF5 enhanced the levels of M1 markers (CD86 and iNOS) and the levels of proin ammatory factors, suggesting that IRF5 promoted the polarization of M1 macrophages. IRF5 is located in the cytoplasm and translocates to the nucleus after LPS stimulation, and the activation of IRF5 can lead to the upregulation of IFN1 transcription [23]. Phosphorylation of IRF3 can induce its translocation into the nucleus and its assembly with binding proteins, leading to promoter binding and activation of the IFN-β gene [24].…”

Section: Discussionmentioning

confidence: 99%

IRF5 promotes the polarization of M1 macrophages and aggravates lung inflammation in connective tissue disease-related interstitial lung disease (CTD-ILD) by regulating IFN-β

Chen,

Ming,

Wang

2023

Preprint

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Background Interferon regulatory factor 5 (IRF5) plays a vital role in proinflammatory M1 macrophages and is involved in their polarization. We aimed to explore the mechanism of action by which IRF5 participates in lung inflammation in connective tissue disease-related interstitial lung disease (CTD-ILD). Methods mRNA and protein levels were determined by qRT‒PCR and Western blotting. Chromatin immunoprecipitation (ChIP) assays were conducted to confirm the targeted relationship between IRF5 and interferon (IFN)-β. ELISA was performed to measure the levels of proinflammatory factors (IL-6, TNF-α, and IL-1β). IRF5 and CD86 expression levels were analyzed by flow cytometry. The nuclear location of IRF5 was detected by immunofluorescence. A double luciferase reporter assay was performed to confirm that IRF5 targets the IFN-β promoter. Hematoxylin and eosin (HE) staining was conducted to assess the histopathology of the lung. Results IRF5 and IFN-β levels in peripheral blood were increased in CTD-ILD patients. IRF5 enhanced IFN-β expression by directly binding to its promoter. IRF5 promoted the M1 polarization of macrophages by activating IFN-β. MS19 suppressed IFN-β expression by inhibiting the activation of IRF5. MS19 repressed the IRF5-induced promotion of LPS-treated RAW264.7 cell M1 polarization. MS19 improved lung inflammation in CTD-ILD model mice by inhibiting the polarization of M1 macrophages via the IRF5/IFN-β axis. Conclusion IRF5 activated IFN-β transcription by targeting the IFN-β promoter, ultimately promoting the polarization of M1 macrophages and aggravating inflammation in CTD-ILD, and the effects were reversed by MS19 treatment.

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Section: Discussionmentioning

confidence: 99%

IRF5 promotes the polarization of M1 macrophages and aggravates lung inflammation in connective tissue disease-related interstitial lung disease (CTD-ILD) by regulating IFN-β

Chen,

Ming,

Wang

2023

Preprint

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“…However, apart from cytoplasmic and extracellular poly(I:C), LPS and Z-DNA also enhanced the expression of CiMex3A, but the efficacy is not very significant in comparison with that of cytoplasmic poly(I:C) ( Figures 1B–E ). LPS participates in the signaling pathway mediated by TRAF6 in grass carp ( 38 ). Z-DNA is the essential stimulation in the ZDHHC1-STING-mediated innate immunity pathway ( 37 ).…”

Section: Discussionmentioning

confidence: 99%

“…CDS regions of grass carp RAB5 (MF598473.1) and RAB7 (MF598474.1) were separately constructed into pDsRed2-C1 (Sangon Biotech, China). PKZ-GFP ( 36 ), ZDHHC1-GFP ( 37 ), TRAF6-GFP ( 38 ), pDsRED2-ER, and pDsRED2-Mitoplasmids (Biofeng) were stored in our lab. All the primers for vector construction are listed in Table 1 .…”

Section: Methodsmentioning

confidence: 99%

Grass Carp Mex3A Promotes Ubiquitination and Degradation of RIG-I to Inhibit Innate Immune Response

Jiang

Sun

et al. 2022

Front. Immunol.

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As one of the Mex3 family members, Mex3A is crucial in cell proliferation, migration, and apoptosis in mammals. In this study, a novel gene homologous to mammalian Mex3A (named CiMex3A, MW368974) was cloned and identified in grass carp, which is 1,521 bp in length encoding a putative polypeptide of 506 amino acids. In CIK cells, CiMex3A is upregulated after stimulation with LPS, Z-DNA, and especially with intracellular poly(I:C). CiMex3A overexpression reduces the expressions of IFN1, ISG15, and pro-inflammatory factors IL8 and TNFα; likewise, Mex3A inhibits IRF3 phosphorylation upon treatment with poly(I:C). A screening test to identify potential targets suggested that CiMex3A interacts with RIG-I exclusively. Co-localization analysis showed that Mex3A and RIG-I are simultaneously located in the endoplasmic reticulum, while they rarely appear in the endosome, mitochondria, or lysosome after exposure to poly(I:C). However, RIG-I is mainly located in the early endosome and then transferred to the late endosome following stimulation with poly(I:C). Moreover, we investigated the molecular mechanism underlying CiMex3A-mediated suppression of RIG-I ubiquitination. The results demonstrated that Mex3A truncation mutant (deletion in the RING domain) can still interact physically with RIG-I, but fail to degrade it, suggesting that Mex3A also acts as a RING-type E3 ubiquitin ligase. Taken together, this study showed that grass carp Mex3A can interact with RIG-I in the endoplasmic reticulum following poly(I:C) stimulation, and then Mex3A facilitates the ubiquitination and degradation of RIG-I to inhibit IRF3-mediated innate antiviral immune response.

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Grass carp (Ctenopharyngodon idellus) TRAF6 up-regulates IFN1 expression by activating IRF5

Cited by 12 publications

References 58 publications

IRF5 promotes the polarization of M1 macrophages and aggravates lung inflammation in connective tissue disease-related interstitial lung disease (CTD-ILD) by regulating IFN-β

IRF5 promotes the polarization of M1 macrophages and aggravates lung inflammation in connective tissue disease-related interstitial lung disease (CTD-ILD) by regulating IFN-β

Grass Carp Mex3A Promotes Ubiquitination and Degradation of RIG-I to Inhibit Innate Immune Response

Effects of three kinds of bacteria on DIGIRR signaling pathway in the Chinese Sturgeon (Acipenser sinensis)

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