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Review
. 2009 Jan 29;122(1):1-11.
doi: 10.1016/j.imlet.2008.11.002. Epub 2008 Dec 6.

Interferons: signaling, antiviral and viral evasion

Cláudio A Bonjardim  1 , Paulo C P Ferreira, Erna G Kroon
Affiliations
Review

Interferons: signaling, antiviral and viral evasion

Cláudio A Bonjardim et al. Immunol Lett. .

Abstract

Interferons (IFNs) were discovered as antiviral agents 50 years ago, and enormous progress has been made since then. Nowadays, IFNs (specifically type I IFNs), have been ascribed as the cytokines that bridge the innate and adaptive immunity soon after the recognition of pathogen-associated molecular patterns (PAMPs) by the infected host. Notably, a unifying mechanism for type I IFN production has been established upon innate immune detection. Thus, TLR 3, 4, 7 and 9 associate endosomal recognition of PAMPs to type I IFN responses, a mechanism that has been shown in plasmacytoid dendritic cells to be dependent on the PI3K/mTOR/S6K pathway. It is worth noting that pathogen recognition triggers a fine-tuned controlled program that not only includes the production of antiviral (IFN) and pro-inflammatory cytokines to initiate the antiviral response but also signals the cessation of the response through the induction of suppressors of cytokine signaling (SOCS). SOCS in turn is under tight regulation of the TAM receptors (protein tyrosine kinase receptors TYRO3, AXL and MER), and activation of which thereby protects the host from the threats of autoimmune diseases.

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Figures

Fig. 1
Fig. 1
IFN-stimulated gene expression via the JAK/STAT signaling pathways. Upon recognition of its cognate receptor (IFNAR1/2), Type I IFNs (only α/β are shown) activate the Janus tyrosine kinases JAK1 and Tyk2. These kinases associate with IFNAR2 and IFNAR1, respectively. JAK1 and Tyk2 in turn tyrosine phosphorylate (Y-P) the receptor chains and create docking sites for STAT2 and STAT1. Following (Y-P), both STATs associate with IRF9 to form the transcriptional regulator ISGF3. ISGF3 then migrates to the nucleus to promote transcription via the regulatory sequence ISRE of the ISGs. IFN-α activation of ISGF3 also requires the acetyltransferase CBP/p300, which interacts with the IFNAR2 at phospho-serine (S-P) 364 and 384. This interaction is followed by lysine (Lys) acetylation at position 399. IRF9 then recognizes the acetylated Lys 399 and binds to the receptor. IRF9, STAT1, and STAT2 are all acetylated by CBP/p300 and then leave the receptor to form ISGF3, which translocates to the nucleus. IFN − β stimulation also leads to the activation of IKKɛ that in turn phosphorylates STAT1, followed by ISGF3 formation. Type II IFN (γ) engages with homodimeric receptors (IFNGR1/2s) to activate JAK1 and JAK2, which are constitutively associated with IFNGR1 and IFNGR2, respectively. The receptor chains are then (Y-P) and create docking sites for STAT1. STAT1 binds to the receptor and is (Y-P) at position 701. A homodimer of STAT1 is formed, resulting in the transcription regulator GAF. GAF in turn translocates to the nucleus, binds to the cis-acting element GAS, and initiates gene transcription. Under certain circumstances, IFN-γ also regulates gene transcription via ISGF3. Type III IFN (λ) interacts with the receptor chains IL-10Rβ and IL-28Rα to transduce signals involving JAK1, STAT1, STAT2, and ISGF3. It also regulates gene expression through ISRE and eventually GAS. IFN-stimulated gene transcription via signaling pathways other than JAK/STAT. IFN-α/β can regulate gene transcription by activating MAPKs. IFN-α stimulation of MEK/ERK leads to CREB/ATF-1 activation and the binding of the cis-acting element CRE to result in α-enolase expression. Activation of the MKK3/6-p38MAPK pathway upon IFN-α treatment leads to gene transcription via ISRE. Stimulation of PI3K by both Type I and II IFNs results in (P) of the serine kinase PKC which then acts as the downstream effector of PI3K and (P) STAT-1 at Ser (S) 727. Upon activation, STAT-1 migrates to the nucleus to initiate STAT-1-driven gene transcription through either ISRE or GAS. Activation of mTOR upon Type I or II IFN stimulation is mediated via PI3K and results in: (i) (P) of p70-S6K, followed by (P) of the ribosomal protein S6 and (ii) (P) and deactivation of the translation repressor 4E-BP1. Both events lead to the initiation of mRNA translation. Abbreviations: ATF1 (activating transcription factor 1), CBP (CREB-binding protein), CRE (cyclic-AMP response element), CREB (CRE binding protein), EIF4E (eukaryotic translation-initiation factor 4E), ERK (extracellular-signal regulated kinase), 4E-BP1 (eukaryotic translation-initiation factor 4E (EIF4E)-binding protein 1), GAF (IFN-γ-activated factor), GAS (IFN-γ-activated sequence), IKKɛ (IκB Kinase Kinase ɛ), IRF (IFN-regulatory factor), ISGF3 (IFN-stimulated gene factor 3), ISRE (IFN-stimulated response element), ISG (IFN-stimulated gene), MAPK (mitogen-activated protein kinase), MEK (MAPK/ERK kinase), MKK (MAPK Kinase Kinase), mTOR (mammalian target of rapamycin), PI3K (phosphatydilinositol-3 kinase), PKC-δ (protein kinase C-δ), p70-S6K (RPS6 kinase), and RPS6 (ribosomal protein S6).
Fig. 2
Fig. 2
Endosomal and cytosolic detection of viral nucleic acid. Endosomal recognition of viral nucleic acid via TLR7,9/MyD88 results in the activation of the TRAF6/IKKα/IRF7 signaling pathway, which culminates in type I/III IFN production. TLR7,9/MyD88 also leads to activation of the PI3K/mTOR/S6K pathway followed by IFNα/β production (c). Downstream targets of TRAF6 also include: (i) TAK1/IKKα/β/NF-κB, a pathway that leads to the expression of inflammatory cytokines (b) and (ii) TAK1/MAPKs. Members of the latter cascade then migrate to the nucleus and activate the transcriptional regulator AP1, which in turn controls the expression of co-stimulatory molecules CD80 and 86 (d). Viral recognition via TLR3/TRIF is followed by the engagement of TRAF3/NAP1 or TANK-TBK1/IKKɛ molecules and the subsequent activation of IRF3. IRF3 translocates to the nucleus and activates transcriptional regulation of type I IFN genes. Full activation of IRF3 also requires PI3K/Akt (e). Signal transduction downstream of TRAF3 also results in the activation of MAPKs and NF-κB and leads to the expression of co-stimulatory molecules (d) and inflammatory cytokines (b). Viral recognition by endosomal TLRs is autophagy dependent. Mice deficient in the autophagy protein atg-5 failed to produce type I IFNs. Cytosolic detection of viral RNA by RIG-1/MDA5 is followed by the interaction of their CARD domains with those of the adaptor protein IPS-1 (MAVS, VISA, or Cardif). Subsequent activation of the TRAF3/NAP-1-TBK1/IKKɛ pathway results in the activation of IRF3/7 and regulation of type I IFN gene expression. Alternatively, instead of NAP-1, the scaffolding proteins TANK or SINTBAD, can also be recruited to transduce downstream signals (a). CARDs need to be ubiquitinated by the TRIM25 E3 ligase in order to transduce downstream signals and type I IFN production. In contrast, signal termination requires RIG-I ubiquitination by the E3 ligase RNF125, which leads to proteasomal degradation (a). The TRAF3/NAP-1-TBK1/IKKɛ pathway is also activated upon recognition of cytosolic DNA by the sensor DAI. Signal transmission downstream of IPS-1 also recruits FADD/RIP1 and IKKα/β to mediate the activation of NF-κB (b) and MAPKs pathways (d). Though not associated with viral recognition, TLR4 also mediates type I IFN production from the endosomal compartment (e). Abbreviations: CARD (caspase activating recruitment domain), DAI (DNA-dependent activator of IFN-regulatory factors), FADD (FAS-associated death domain), IKK (IκB Kinase Kinase), IPS (IFNβ-promoter stimulator) IRAK (IL-1 receptor-associated kinase), MAPKs (mitogen-activated protein kinases), MDA5 (melanoma differentiation associated gene 5), MyD88 (myeloid-differentiation primary-response gene 88), NAP-1 (NAK-associated protein 1), NF-κB (nuclear factor κB), (PI3K) phosphotidylinositol 3-kinase, RIG-1 (retinoic acid-induced gene 1), RIP1 (receptor-interacting protein 1), TAB (TAK1-binding protein), TAK1 (TGF-β-activated kinase 1), TBK (tank-binding kinase), TRAF (TNF receptor-associated factor), TRAM (TRIF-related adaptor molecule), TRIF (TIR domain-containing adaptor protein inducing IFN-β).
Fig. 3
Fig. 3
Amplifying IFN production and negative regulation exerted by the TAM receptor Ax1 and SOCS. Upon recognition of a viral nucleic acid via the endosomal TLRs, Type I IFNs are produced and secreted (early events—see Fig. 1). They then act in an autocrine/paracrine manner through the IFNAR/JAK/STAT1/IRF7 pathway to amplify both IFN production (delayed events) and antiviral effects through the expression of 2′–5′OAS, PKR, ADAR-1, TRIM 5α, ISG15, and MX. Stimulation of RNase L downstream of the 2′–5′OAS pathway is followed by the degradation of cellular ss-RNAs, recognition by RIG-1 and MDA5, and production of IFNs. Upon viral infection in DCs, IRF8 associates with RNAP II at the IFN promoters to increase IFN transcription and production. The translation repressor 4EBP1/2 exerts a negative regulatory role over IRF7 protein expression and Type I IFN production. Stimulation of the IFNAR/JAK/STAT1 pathway also leads to the up-regulation of the TAM receptor Axl, which in turn accumulates at the cell surface, physically associates with the IFNAR, and usurps the IFNAR-STAT-1 pathway to stimulate SOCS1 and SOCS3 transcription. These actions thereby exert a negative regulatory role through the inhibition of both TLR and TLR-induced cytokine receptor pathways to maintain immune homeostasis. Abbreviations: ADAR-1 (adenosine deaminase acting on RNA 1), 4EBP1/2 (eukaryotic translation-initiation factor 4E (EIF4E)-binding protein 1/2), ISG15/56 (IFN-stimulated gene 15/56), MDA5 (melanoma differentiation associated gene 5), MX (myxovirus resistance), 2′–5′OAS (2′–5′oligoadenylate synthetase), PKR (double-stranded RNA-dependent protein kinase), RNAP II (RNA polymerase II), RIG-1 (retinoic acid-induced gene 1), SOCS (suppressors of cytokine signaling), TAM receptor (protein tyrosine kinases TYRO3, AXL and MER), TRIM 5α (tripartite motif protein).
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