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Airway Epithelial and Early Innate Immune Responses toVirus Infections
Published in Sunit K. Singh, Human Respiratory Viral Infections, 2014
Alan Chen-Yu Hsu, Su-Ling Loo, Faezeh Fathi Aghdam, Kristy Parsons, Philip M. Hansbro, Peter A. B. Wark
TLR3-mediated NF-κB activation and signaling has also been demonstrated to participate in type I and III IFN induction and signaling. After viral infection transcription factors NF-κB, IRF3, and activating transcription factor (ATF) 3 bind to a structural protein named high mobility group (HMG)-I protein, they form a transcription factor-enhancer complex named the IFN-β enhanceosome. This complex then binds to the transcription coactivator cAMP response element-binding (CREB) binding protein (CBP)/p300, forming another complex called transcription preinitiation complex (PIC). PIC then facilitates the binding of RNA polymerase II to the transcription start site of IFN-β gene, thereby driving the induction of IFN-β.37,38 NF-κB has also been shown to drive the induction of type III IFN after infection. A cluster of NF-κB binding sites has been found on human IFN-λ1 promoter, and NF-κB and IRF3 have been shown to be critical in the induction of IFN-λ1 during viral infection.39
Cancer-specific type-I interferon receptor signaling promotes cancer stemness and effector CD8+ T-cell exhaustion
Published in OncoImmunology, 2021
Wang Gong, Christopher R. Donnelly, Blake R. Heath, Emily Bellile, Lorenza A. Donnelly, Hülya F. Taner, Luke Broses, J. Chad Brenner, Steven B. Chinn, Ru-Rong Ji, Haitao Wen, Jacques E. Nör, Jie Wang, Gregory T. Wolf, Yuying Xie, Yu Leo Lei
Although the activation of the IFN-I pathway is essential for myeloid M1-like polarization and cross-priming of T-cells, it is equally important to understand the mechanisms underpinning the discrepancies in these different studies. Unlike the type II and type III interferons, whose production is restricted to a small collection of cell types, IFN-I is highly evolutionarily conserved, and almost all normal cell types express IFN-I induction machinery and its receptor IFNAR1. The activation of a spectrum of pattern recognition receptors, including the Toll-like receptors (TLRs), RNA sensors such as DExD/H-Box Helicase 58 (DDX58, aka Retinoic Acid-inducible Gene I or RIG-I), Interferon Induced with Helicase C Domain 1 (IFIH1, aka Melanoma Differentiation-Associated Protein 5 or MDA5), or DNA sensor cyclic GMP-AMP Synthase (cGAS), leads to the phosphorylation of IRF3 and NF-κB. Nuclear phospho-IRF3 and phospho-p65 form an enhanceosome to drive the generation of IFN-I, which includes 13 subtypes of IFN-α, IFN-β, IFN-ω, IFN-ϵ, and IFN-κ. IFN-I functions in an autocrine or paracrine fashion to engage its receptor constituted by IFNAR1 and IFNAR2 on the plasma membrane. Upon activation, tyrosine kinases Tyrosine Kinase 2 (TYK2) and Janus Kinase 1 (JAK1) are phosphorylated, which leads to the phosphorylation of the Signal Transducers and Activators of Transcription (STAT)1 and STAT2. Within the IFNAR1 transcriptional program, MX Dynamin Like GTPase 1 (MX1) is a transgene that is specifically induced by IFN-I and used as a sensitive surrogate marker for IFNAR1 signaling.