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Signaling in the Type I Interferon Antiviral Innate Immune Response

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Signaling in the Type I Interferon Antiviral Innate Immune Response Signaling in the type I interferon antiviral innate Most vertebrate cells respond to viral infection by producing and sensing NF-κB, transcription factors that trigger the expression of genes encod- immune response type I interferon (IFN), which establishes an antiviral state characterized ing type I IFN proteins and other mediators of innate immune activation. by inhibition of viral replication, apoptosis of infected cells, and stimu- Type I IFN proteins bind to the type I IFN receptor and activate Janus ki- David E Levy & Isabelle J Marié lation of innate immune mechanisms that augment subsequent adaptive nase–signal transducer and activator of transcription (Jak-STAT) signaling 4,2 immune responses. Vertebrate cells detect virus infection either via the and formation of the trimeric transcription factor complex ISGF3, which #$ cytoplasmic RNA helicase sensors RIG-I and MDA-5, the cytoplasmic promotes expression of antiviral effector proteins as well as proteins that -$ DNA-dependent activator of IFN-regulatory factor (DAI), and/or via a positively and negatively modulate subsequent signaling. This poster high- pathway initiated by transmembrane Toll-like receptors (TLRs). All path- lights common and distinct components of these pathways that together ways culminate in activation of interferon regulatory factor (IRF) and lead to a highly orchestrated innate immune response to viral infection. 42!- -!, 42)& -Y$ Pathogen recognition: the cytosolic pathway and TYK2 kinases, respectively. IFN binding results in kinase Many viruses replicate in the cell cytoplasm after invading cells activation, receptor phosphorylation, and STAT protein recruit- )2!+ 2)0 by fusion either with the plasma membrane or with endosomal ment and tyrosine phosphorylation. The IFN receptor also 42!& .326 0326 DS$.! 42!& membranes after endocytotic uptake. Within the cytoplasm, activates PI3K and MAPK, which trigger auxiliary signals im- viral nucleic acid stimulates innate immune signaling. Spe- portant for augmenting the IFN response. STAT proteins exist -!0+ 4!" 4!" as latent cytoplasmic dimers which, after tyrosine phosphoryla- 2)' ) -$! $!) cifi cally, DNA viruses are detected by the DAI DNA sensor, 42)- which, after contact with dsDNA, associates with the kinase tion, undergo a major conformational change resulting in a shift 4"+ 4!+ TBK1 and the transcription factor IRF3 and provokes transcrip- from an anti-parallel structure unable to bind DNA to a parallel tion of the gene encoding IFN-β. Negative-strand RNA viruses dimer structure stabilized by mutual SH2 domain–phosphoty- 5B -!63 )++G )++E 4"+ rosine interactions. Type I IFN signaling preferentially acti- 2.& stimulate the RIG-I RNA helicase, which distinguishes viral ! from endogenous RNA by the presence of a 5′ triphosphate vates STAT1 and STAT2, which form heterodimers. STAT2 is DS2.! &!$$ 42!& )2& )++A )++B .!0) moiety in viral ssRNA. Positive-strand RNA viruses, perhaps constitutively associated with IRF9. Thus, the ISGF3 ternary 4!.+ )++G )2& because of their double-stranded character, are recognized by complex of STAT1, STAT2 and IRF9 binds to and activates the the related helicase MDA-5. RNA binding triggers a conforma- interferon-stimulated response element (ISRE), a composite 42!& .!0) 0+ tional change and exposure of paired N-terminal CARD do- STAT-IRF binding site, which is usually found in the promoter 4,2 4"+) )++E )2& mains in RIG-I and MDA-5, thus allowing interaction between region of IFN-inducible genes. 42)& the activated helicases and the mitochondrial adaptor protein )2& 4!" 4!" MAVS. Interactions between RNA helicases and MAVS are Nuclear processes: transcription and transport !+4 2)0 42!& potentiated by TRIM25-mediated ubiquitination, and signaling Phosphorylation of IRF, NF-κB, AP-1 and STAT transcription #ASPASE4!+ *NK 42!& 3RC via RIG-I and MDA-5 is suppressed by the ubiquitin E3 ligase factors results in their nuclear translocation and modulation 4!" 4!" RNF125 and the deubiquitinating enzyme A20. MAVS re- of their capacity to bind DNA and recruit essential coactivator 5B cruits the adaptor proteins FADD, TRAF3 and TRAF6, and the proteins (also their homodimerization, in the case of IRF tran- )++G )K" 4!+ )++E 4"+ kinase complexes TAB-TAK1, IKKα-IKKβ-IKKγ and IKKγ- scription factors). Conformational shifts that uncover nuclear TANK-NAP1-TBK1-IKKε, that collectively lead to activation localization sequences and inhibit nuclear export sequences of the AP-1, NF- B and IRF transcription factors. IRF3 is an )++A )++B P P κ augment nuclear accumulation of these transcription factors. .!0) important target of phosphorylation during early phases of the -!0+ AP-1, NF-κB and dimers of IRF3 and/or IRF7 bind coopera- response and is essential for production of IFN-β and a limited tively to the IFN-β enhanceosome, establishing a compact )++G set of IFN-α isoforms; IRF7 becomes a major phosphorylation structure that permits coactivator recruitment. IRF3 homodi- 0IN target after its production during the positive feedback of initial mers can bind to a limited set of IFN- promoters, whereas the )2& )2& α )++A )++B IFN signaling. broader sequence-binding specifi city of IRF7 allows IRF7-con- C *UN !4& taining dimers to bind to all IFN-α promoters. ISGF3 recruits P P )&. B Pathogen recognition: the transmembrane pathways the coactivators GCN5, TAF4 and p300-CBP as well as the TLR3, TLR7 and TLR9 reside in endosomal compartments coactivator Mediator complex. Newly transcribed mRNA is !0 )2& .& K" and recognize pathogen nucleic acids produced either during exported to the cytoplasm for translation through nuclear pores; viral replication or, in macrophages and dendritic cells, after evidence supports selectivity of mRNA export mediated by phagocytosis of dying cells or viral particles. TLR3 recognizes transport proteins such as Nup96, Nup98 and Rae1, which are P P dsRNA and activates IFN gene induction through the TRIF also IFN inducible and therefore participate in positive feed- )2& )2& ! adaptor protein. Phosphorylation of tyrosine residues in the back of IFN responses. )K" 4.& cytoplasmic domain of TLR3 (probably by the kinase c-Src) .& K" ), -!0+ results in recruitment of PI3K, TRAF3 and TRAF6 and of the Positive and negative feedback )&. A RIP1-TAB-TAK1 complex, which activate IRF3, NF-κB and IFN antiviral signal transduction pathways are subject to AP-1. TLR7 and TLR9 recognize ssRNA and unmethylated complex positive and negative feedback, because many signal- )++G )3'& .UP CpG DNA, respectively, and directly activate IRF7 in a manner ing components are themselves the products of IFN-stimulated 2AE )++A )++B dependent on the MyD88, IRAK and TRAF adaptor proteins )3' genes. Cytosolic signaling is augmented by IFN-induced RIG- 34!4 )++E 3/#3 and the kinase IKKα. Expression of TLR3, TLR7 and TLR9 is 1, MDA-5, DAI, TRIM25, IKKε and IRF7 and is suppressed 2.& )32% 34!4 2)' ) augmented by IFN. TLR3 preferentially induces IFNβ, whereas by the IFN-induced ubiquitin E3 ligase RNF125, which targets 4!" -$! 4!+ TLR7 and TLR9 are responsible for strong production of IFNα RIG-I for degradation. Likewise, NF-κB responses are inhib- 34!4 3/#3 42!& 4!" )2& (and perhaps IFNβ). TLR4 responds primarily to microbial ited by NF-κB–stimulated transcription of the gene encoding )&.!2) M2.! )2!+ *AK 34!4 )2& products from Gram-negative bacteria and, through signaling IκBα. IFN signaling is augmented by IFN-dependent induction )2& 4RANSPORT -Y$ 34!4 via the MyD88 and TRIF adaptor proteins, activates expression )&. -ACHINERY of STAT1, STAT2 and IRF9 and is negatively regulated by in- 4YK of NF-κB–dependent infl ammatory cytokines and IRF3-depen- duction of SOCS1, an inhibitor of Jak kinase catalytic function. .UCLEAR0ORE )2!+A )&.!2)) dent IFN-β. TLR4 also responds to some viral products, includ- Cytoplasmic export of IFN-stimulated transcripts is augmented 34!4 42, ing vesicular stomatitis virus glycoprotein G. )2& by the IFN-dependent expression of the nuclear pore and mRNA transport factors Nup96, Nup98 and Rae1. Additional 42, SS2.! IFN signaling through the Jak-STAT pathway negative regulators include LGP2, which competes with RIG-1 .EGATIVE&ACTORS 0OSITIVE&ACTORS All type I IFN proteins bind to a cell surface receptor complex and MDA-5 for binding to viral nucleic acid, and Pin1, which 2.& 2)' ) composed of the IFNARI and IFNARII chains linked to Jak1 inhibits activated IRF3. 3/#3 -$! DS$.! )2& !NTIVIRAL )++E /!3 .UP 0+2 2AE )3' -X Further reading Levy, D.E. & Darnell, J.E. Jr. STATs: Vilcek, J. Fifty years of interferon We gratefully acknowledge NIH grants R01- Colonna, M. TLR pathways and IFN- transcriptional control and biological research: aiming at a moving target. Im- AI28900, R01-CA90773, R01-AI46503 and regulatory factors: to each its own. Eur. J. impact. Nat. Rev. Mol. Cell. Biol. 3, munity 25, 343–348 (2006). U54-AI057158 for research support. Immunol. 37, 306–309 (2007). 651–662 (2002). PBL InterferonSource, a division of Pestka Biomedical Laboratories, Inc. based in A20; AP-1, activator protein 1; ATF-2, activating transcription factor 2; dsRNA, Pin1, peptidyl-prolyl isomerase 1; PKR, protein kinase R; PSRV, positive-strand Yoneyama, M. & Fujita, T. Function of Edited by Jamie Wilson, Christine Borowski and Douglas Braaten. Copyedited by Rebecca Barr. Honda, K. & Taniguchi, T. IRFs: master Levy, D.E. & Marie, I.J. RIGging an an- RIG-I-like receptors in antiviral innate Piscataway, New Jersey, USA, is the world’s largest producer of interferons and re- double-stranded RNA; FADD, Fas-associated death domain; IFN, interferon; IκBa, RNA virus; RIG-I, retinoic acid–inducible protein 1; RIP1, receptor-interacting pro- Designed by Lewis Long. regulators of signaling by Toll-like recep- tiviral defense—it’s in the CARDs. Nat. immunity. J. Biol. Chem. 282, 15315– lated products for the life sciences research market. Founded in 1990 by Dr. Sidney inhibitor of NF-κB; IKK, IκB kinase; IL-6, interleukin 6; IRAK, interleukin 1 re- tein 1; RNF125, ring fi nger protein 125; Src, c-Src; ssRNA, single-stranded RNA; tors and cytosolic pattern-recognition Immunol.
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