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

Zhao, Xueyan; Huo, Ruixuan; Yan, Xiaolong; Xu, Tianjun

doi:10.3389/fimmu.2018.00867

Cited by 30 publications

(10 citation statements)

References 49 publications

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“…EPC and HEK293 cells were transfected with various plasmids using Lipofectamine 3000 TM (Invitrogen). In addition, proteasome inhibitor MG132 (sigma) or cycloheximide (CHX) (Beyotime) was added into the medium at 24 h post transfection and used at a final concentration of 30 µM/ml and 100 µg/ml (29).…”

Section: Cell Culture and Transient Transfectionsmentioning

confidence: 99%

IRF3 and IRF8 Regulate NF-κB Signaling by Targeting MyD88 in Teleost Fish

et al. 2020

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MyD88 is a conserved intracellular adaptor, which plays an important role in the innate immune system. MyD88 transmits signals for downstream of toll-like and IL-1 receptors to activate NF-κB signaling pathway, which is tightly controlled in the immune response to maintain immune intensity and immune homeostasis at different stages. NF-κB signaling pathway has been extensively studied in mammals, but regulatory molecular mechanism is still unclear in teleost fish. We determined that IRF3 and IRF8 can regulate MyD88-mediated NF-κB signaling pathway in fish. Interestingly, MyD88 is precisely regulated by IRF3 and IRF8 through the same mechanism but in completely opposite ways. IRF3 promotes MyD88-mediated NF-κB signaling pathway, whereas IRF8 inhibits the signaling pathway. MyD88 is regulated via ubiquitin-proteasome degradation, whereas IRF3 or IRF8 inhibited or promoted MyD88 degradation in this pathway. Specifically, in the early stage of lipopolysaccharide (LPS) stimulation or Vibrio infection, up-regulation of IRF3 and down-regulation of IRF8 eventually increased MyD88 expression to activate the NF-κB signaling pathway to trigger immune response. In the late stage of stimulation, down-regulated IRF3 and up-regulated IRF8 synergistically regulate the expression of MyD88 to a normal level, thus maintaining the immune balance of homeostasis and preventing serious damage from persistent over-immunization. This study presents information on Myd88-NF-κB signaling pathway in teleost fish and provides new insights into its regulatory mechanism in fish immune system.

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Section: Cell Culture and Transient Transfectionsmentioning

confidence: 99%

IRF3 and IRF8 Regulate NF-κB Signaling by Targeting MyD88 in Teleost Fish

et al. 2020

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“…For example, LPS-induced NF-κB activation and TNF production were inhibited by recombinant sTLR4 expressed by macrophages in vitro . In addition, recent investigation in cells of mammals and fish demonstrated that IRF3 negatively regulates the TLR-mediated NF-κB signaling pathway by targeting TRIF for ubiquitination and degradation (32). In brief, hosts initiate robust activation of the innate immune system to guard against pathogens, including LPS, and mobilize a variety of extracellular and intracellular negative feedback pathways to avoid an overstimulated inflammatory state.…”

Section: Role Of Mir-146a In the Toll-like Receptor 4 (Tlr4) Signalinmentioning

confidence: 99%

Multiple roles of microRNA‑146a in immune responses and hepatocellular carcinoma (Review)

Wang

et al. 2019

Oncol Lett

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MicroRNAs (miRNAs/miRs), consisting of ~22 nucleotides of single-stranded RNA, participate in post-transcriptional gene regulation by binding to the 3′-untranslated region (UTR) of mRNAs, repressing their translation and promoting their degradation. Studies have shown that certain miRNAs play a key role in the control of various cellular activities, such as inhibiting inflammation, modulating cell differentiation and suppressing cancer growth. The role of miR-146a in the immune response and in the pathogenesis of hepatocellular carcinoma (HCC) has also been investigated. Although some studies have shown that increased miR-146a levels are associated with HCC, others have revealed that miR-146a suppresses cancer cell proliferation, invasion and metastasis. Toll-like receptor 4 (TLR4) signaling has an important role in regulating innate and adaptive immune responses. In addition, TLR4 is functionally expressed in HCC cells and promotes HCC cell proliferation, which can be regulated by miR-146a. The present review focuses on the recent progress in analyzing the multiple roles of miR-146a in mediating the TLR4 pathway and adaptive immune response. Finally, the function of miR-146a in the pathogenesis of HCC is also discussed.

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“…In addition to the regulators that can regulate TRIF in mammals, Zhao et al has recently found a class of regulatory factors that can negatively regulate the TRIF-mediated NF-kB signaling pathway in teleost. They have found that interferon regulatory factor 3 (IRF3) and IRF9 can serve as negative regulators of TRIF to regulate its mediated immune response and prevent the excessive immune response of the body [ 19 , 20 ]. Despite considerable research on mammalian TRIF in antiviral immunity and anti-tumor, research on TRIF in lower vertebrates still has many challenges; therefore, exploration of the regulatory mechanism of TRIF-mediated signal transduction is urgently needed.…”

Section: Introductionmentioning

confidence: 99%

Circular RNA circDtx1 regulates IRF3-mediated antiviral immune responses through suppression of miR-15a-5p-dependent TRIF downregulation in teleost fish

et al. 2021

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Circular RNAs (circRNAs) represent a class of widespread and diverse covalently closed circular endogenous RNAs that exert crucial functions in regulating gene expression in mammals. However, the function and regulation mechanism of circRNAs in lower vertebrates are still unknown. Here, we discovered a novel circRNA derived from Deltex E3 ubiquitin ligase 1 (Dtx1) gene, namely, circDtx1, which was related to the antiviral responses in teleost fish. Results indicated that circDtx1 played essential roles in host antiviral immunity and inhibition of SCRV replication. Our study also found a microRNA miR-15a-5p, which could inhibit antiviral immune response and promote viral replication by targeting TRIF. Moreover, we also found that the antiviral effect inhibited by miR-15a-5p could be reversed with the circDtx1. In mechanism, our data revealed that circDtx1 was a competing endogenous RNA (ceRNA) of TRIF by sponging miR-15a-5p, leading to activation of the NF-κB/IRF3 pathway, and then enhancing the innate antiviral responses. Our results indicated that circRNAs played a regulatory role in immune responses in teleost fish.

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

Cited by 30 publications

References 49 publications

IRF3 and IRF8 Regulate NF-κB Signaling by Targeting MyD88 in Teleost Fish

IRF3 and IRF8 Regulate NF-κB Signaling by Targeting MyD88 in Teleost Fish

Multiple roles of microRNA‑146a in immune responses and hepatocellular carcinoma (Review)

Circular RNA circDtx1 regulates IRF3-mediated antiviral immune responses through suppression of miR-15a-5p-dependent TRIF downregulation in teleost fish

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