Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6.
ABSTRACT Toll-like receptors (TLRs) are involved in the recognition of microbial pathogens. A subset of TLRs, TLR7, TLR8 and TLR9, induces antiviral responses by producing interferon-alpha (IFN-alpha). Production of IFN-alpha is dependent on the Toll-interleukin-1 receptor domain-containing adaptor MyD88. Here we show that MyD88 formed a complex with the transcription factor IRF7 but not with IRF3. The death domain of MyD88 interacted with an inhibitory domain of IRF7, and this interaction resulted in activation of the IFN-alpha-dependent promoters. Furthermore, the adaptor molecule TRAF6 also bound and activated IRF7. Ubiquitin ligase activity of TRAF6 was required for IRF7 activation. These results indicate that TLR-mediated IFN-alpha induction requires the formation of a complex consisting of MyD88, TRAF6 and IRF7 as well as TRAF6-dependent ubiquitination.
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ABSTRACT: The innate immune response is the first line of defence against viruses, involving the production of type I IFN (IFN-α/β) and other pro-inflammatory cytokines that control the infection. It also shapes the adaptive immune response generated by both T and B cells. Production of type I IFN occurs both in vivo and in vitro in response to Bluetongue virus (BTV), an arthropod-borne virus. However, the mechanisms responsible for the production of IFN-β in response to BTV remained unknown until recently and are still not completely understood. In this review, we describe the recent advances in the identification of cellular sensors and signalling pathways involved in this process. The RNA helicases retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) were shown to be involved in the expression of IFN-β as well as in the control of BTV infection in non-hematopoietic cells. In contrast, induction of IFN-α/β synthesis in sheep primary plasmacytoid dendritic cells (pDCs) required the MyD88 adaptor independently of the Toll-like receptor 7 (TLR7), as well as the kinases dsRNA-activated protein kinase (PKR) and stress-activated protein kinase (SAPK)/Jun N-terminal protein kinase (JNK). As type I IFN is essential for the establishment of an antiviral cellular response, most of viruses have elaborated counteracting mechanisms to hinder its action. This review also addresses the ability of BTV to interfere with IFN-β synthesis and the recent findings describing the non-structural viral protein NS3 as a powerful antagonist of the host cellular response.Virus Research 11/2013; 182. DOI:10.1016/j.virusres.2013.10.027 · 2.83 Impact Factor
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ABSTRACT: Protein post-translational modifications (PTMs) are central to the host innate immune regulations. Dynamically, PTMs fine-tune the spatial and temporary responses of immune- and non-immune-cells, in accordance with extracellular and intracellular stresses. Ubiquitin and ubiquitin-like proteins (Ubls) are emerging as the important multi-functional signals, controlling the activation, stability, affinity and location of many signaling proteins. Recent investigations, at the molecular-cellular-animal models, have shed new light on the versatility of the ubiquitin, SUMO and ISG15, for shaping the strength and duration of the innate immune responses. This review summarizes our current knowledge on the functions and regulatory mechanisms of the ubiquitin and Ubls in the innate immunity, the first line of host defense against microbial infection.Cytokine & growth factor reviews 08/2013; 24(6). DOI:10.1016/j.cytogfr.2013.07.002 · 6.54 Impact Factor
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ABSTRACT: Current therapies for systemic lupus erythematosus (SLE), a debilitating, potentially lethal, multifactorial systemic autoimmune disease, are limited to suppressing disease activity and are associated with multiple adverse effects. Recent advances in basic and translational sciences have elucidated a crucial role for the interferon-alpha (IFNα) pathway in the pathogenesis of this enigmatic disease. The so-called "type I interferon signature" has emerged as a major risk factor for disease activity of SLE. Multiple genes encoding for molecules within the type I interferon pathway have been associated with SLE in genome wide association studies. In addition, innate immune receptors are thought to be triggered by either endogenous and/or exogenous stimuli that lead to hypersecretion of IFNα. We review the multiple emerging treatment strategies targeting IFNα-related pathways. These include monoclonal antibodies against IFNα, anti-IFNα antibody-inducing vaccines, and inhibitors of Toll-like receptors. We also summarize the current status of these pharmaceutical agents in early clinical trials.Clinical Immunology 04/2012; 143(3):210-21. DOI:10.1016/j.clim.2012.03.005 · 3.99 Impact Factor