A Novel IRAK1–IKKε Signaling Axis Limits the Activation of TAK1–IKKβ Downstream of TLR3

Bruni, Daniela; Sebastià, Jordi; Dunne, Susan; Schröder, Martina; Butler, Margaret H.

doi:10.4049/jimmunol.1202042

Cited by 20 publications

(22 citation statements)

References 40 publications

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“…MST1 directly bound to and phosphorylated IL-1 receptor-associated kinase 1 (IRAK1), leading to the degradation of IRAK1 (55). IRAK1 has been proven to negatively regulate MyD88-, TRIF-, and RIG-Imediated IFN-β production (56,57). Therefore MST1-mediated degradation of IRAK1 potentiated IRF3 activation and IFN-β production (55).…”

Section: Hippo-yap and Ifn-i Signalingmentioning

confidence: 99%

The Crosstalk Between Hippo-YAP Pathway and Innate Immunity

et al. 2020

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Recognition of pathogen-associated molecular patterns (PAMPs) triggers expression of antiviral interferons and proinflammatory cytokines, which functions as the frontier of host defense against microbial pathogen invasion. Hippo-YAP pathway regulates cell proliferation, survival, differentiation and is involved in diverse life processes, including tissue homeostasis and tumor suppression. Emerging discoveries elucidated that the components of Hippo-YAP pathway, such as MST1/2, NDR1/2, and YAP/TAZ played crucial regulatory roles in innate immunity. Meanwhile the innate immune signaling also exhibited regulatory effect on Hippo-YAP pathway. As for the importance of these two pathways, it would be interesting to figure out the deeper biological implications of their interplays. This review focuses on the regulation between Hippo-YAP pathway and innate immune signaling. We also propose the possible contribution of these interplays to tumor development.

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Section: Hippo-yap and Ifn-i Signalingmentioning

confidence: 99%

The Crosstalk Between Hippo-YAP Pathway and Innate Immunity

et al. 2020

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“…The IKKi/IKKe-IRAK1 interaction downstream of TLR3 is described in ref. [239]. MD2, lymphocyte antigen 96; RAC1, Ras-related C3 botulinum toxin substrate 1; TAB, TAK1-binding protein.…”

Section: Positive Regulators Of Trif-dependent Tlr Signalingmentioning

confidence: 99%

TRIF-dependent TLR signaling, its functions in host defense and inflammation, and its potential as a therapeutic target

Ullah

Sweet

Mansell

et al. 2016

Journal of Leukocyte Biology

155

108

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Toll/IL-1R domain-containing adaptor-inducing IFN-β (TRIF)-dependent signaling is required for TLR-mediated production of type-I IFN and several other proinflammatory mediators. Various pathogens target the signaling molecules and transcriptional regulators acting in the TRIF pathway, thus demonstrating the importance of this pathway in host defense. Indeed, the TRIF pathway contributes to control of both viral and bacterial pathogens through promotion of inflammatory mediators and activation of antimicrobial responses. TRIF signaling also has both protective and pathologic roles in several chronic inflammatory disease conditions, as well as an essential function in wound-repair processes. Here, we review our current understanding of the regulatory mechanisms that control TRIF-dependent TLR signaling, the role of the TRIF pathway in different infectious and noninfectious pathologic states, and the potential for manipulating TRIF-dependent TLR signaling for therapeutic benefit.

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“…(D and E) Relative ratio of phospho-STAT1/PCNA (nuclear loading control) in WT and IRAK1 2/2 BMDM at 1 and 3 h following poly(I:C) and LPS stimulation, as determined by densitometric analysis of three independent experiments. (35). In this study, we observed no increase in IRF3 activation in IRAK1 2/2 BMDM following TLR4 ligand stimulation (Supplemental Fig.…”

Section: Irak1 Regulates Irf1 and Irf9 Key Regulators Of Il-27p28 Exmentioning

confidence: 48%

“…MRT67307 inhibited TLR3/4-induced IFN-b expression in WT BMDM and in LPS-stimulated IRAK1 2/2 macrophages. In contrast, we detected high levels of IFN-b in poly(I:C)-stimulated IRAK1 2/2 compared with WT macrophages (35), which we found to remain high following MRT67307 treatment (Fig. 1D).…”

Section: Resultsmentioning

confidence: 67%

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IRAK1 Limits TLR3/4- and IFNAR-Driven IL-27 Production through a STAT1-Dependent Mechanism

Bruni

Dignam

Dunne

et al. 2018

The Journal of Immunology

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IL-27 is a cytokine exerting pleiotropic immunomodulatory effects on a broad spectrum of immune cells. Optimal IL-27 production downstream of TLR3/4 ligand stimulation relies on autocrine type I IFN signaling, defining a first and second phase in IL-27 production. This work shows that IL-1 receptor-associated kinase 1 (IRAK1) limits TLR3/4- and IFNAR-induced IL-27 production. At the mechanistic level, we identified IRAK1 as a novel regulator of STAT1, IRF1, and IRF9. We found hyperactivation of STAT1 together with increased nuclear levels of IRF1 and IRF9 in IRAK1-deficient murine macrophages compared with control cells following stimulation with LPS and poly(I:C). IRAK1-deficient human microglial cells showed higher basal levels of STAT1 and STAT2 compared with control cells. Blocking the kinase activity of TBK1/IKKε in IRAK1 knockdown human microglial cells reduced the high basal levels of STAT1/2, uncovering a TBK1/IKKε kinase-dependent mechanism controlling basal levels of STAT1/2. Stimulating IRAK1 knockdown human microglial cells with IFN-β led to increased IL-27p28 expression compared with control cells. In IRAK1-deficient murine macrophages, increased IL-27 levels were detected by ELISA following IFN-β stimulation compared with control macrophages together with increased nuclear levels of p-STAT1, IRF1, and IRF9. Treatment of wild-type and IRAK1-deficient murine macrophages with fludarabine similarly reduced TLR3/4-induced IL-27 cytokine levels. To our knowledge, this work represents the first report placing IRAK1 in the IFNAR pathway and identifies IRAK1 as an important regulator of STAT1, controlling IL-27 production downstream of TLR3/4 and IFNAR signaling pathways.

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A Novel IRAK1–IKKε Signaling Axis Limits the Activation of TAK1–IKKβ Downstream of TLR3

Cited by 20 publications

References 40 publications

The Crosstalk Between Hippo-YAP Pathway and Innate Immunity

The Crosstalk Between Hippo-YAP Pathway and Innate Immunity

TRIF-dependent TLR signaling, its functions in host defense and inflammation, and its potential as a therapeutic target

IRAK1 Limits TLR3/4- and IFNAR-Driven IL-27 Production through a STAT1-Dependent Mechanism

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