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. 2019 Dec 5;217(1):e20190459. doi: 10.1084/jem.20190459

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© 2019 Chen et al.

This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

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Figure 1. — Simplified schematic of type-I IFN induction and major IFNAR signaling pathways. Type-I IFNs are induced by nucleic acid or LPS activation of a variety of PRRs, including cytosolic nucleic acid sensors and TLRs. Activation of PRRs results in nuclear translocation of IRFs, which bind to the promoter region of type-I IFNs. IRF3-mediated IFN expression could be induced by STING (via cGAS), RIG-1, MDA5, TLR3, and TLR4 (through TRIF) while ligand engagement of TLR7/8 and TLR9 activate IRF7 and/or IRF5 via MyD88. Cytokines such as TNF can also induce type-I IFN expression through the TNFR-IRF1 signaling pathway. Secreted type-I IFNs bind autocinely/paracrinely to the IFNAR complex composed of IFNAR1 and IFNAR2, which consequently triggers cross-phosphorylation of TYK2 and JAK1 and activates different STAT homo/heterodimers controlling distinct transcription programs. ISGF3 consists of STAT1, STAT2, and IRF9 and binds to IFN-stimulated response element (ISRE) sequences upstream of ISGs and IRF7, while STAT1 homodimer induces IRF1 and pro-inflammatory gene expression via GASs binding. dsRNA, double-stranded RNA; ssRNA, single-stranded RNA.