Key Points
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There are two main classes of interferon (IFN): type I IFNs and type II IFN. There are many type I IFNs, including IFN-α, IFN-β and IFN-ω, and all of these bind a common cell-surface receptor. IFN-γ, the only type II IFN, initiates signalling by binding a distinct receptor at the cell surface.
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Type I and type II IFNs activate both common and distinct STAT (signal transducer and activator of transcription) complexes, which regulate the transcription of target genes.
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In addition to the classical Janus activated kinase (JAK)–STAT-signalling pathways, both type I and type II IFNs activate several other signalling cascades.
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CRKL, a member of the CRK family of proteins, is activated by both type I and type II IFNs, and it functions as a nuclear adaptor for STAT5 and/or as an upstream regulator of a signalling pathway that involves the guanine-nucleotide-exchange factor C3G and RAP1.
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The mitogen-activated protein kinase p38 is activated by type I IFNs and has a crucial role in the type-I-IFN-dependent transcription of genes and in the generation of the antiproliferative and antiviral effects of type I IFNs.
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Both type I and type II IFNs regulate activation of the phosphatidylinositol 3-kinase (PI3K)-signalling pathway. One of the downstream effectors of PI3K is protein kinase C-δ, which functions as a serine kinase for STAT1.
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At least two distinct pathways for the regulation of mRNA translation are activated downstream of IFN-activated PI3K and mammalian target of rapamycin (MTOR). One involves activation of p70 S6 kinase and phosphorylation of ribosomal protein S6, and the other involves phosphorylation and deactivation of the translational repressor 4EBP1 (eukaryotic translation-initiation factor 4E (EIF4E)-binding protein 1).
Abstract
Interferons are cytokines that have antiviral, antiproliferative and immunomodulatory effects. Because of these important properties, in the past two decades, major research efforts have been undertaken to understand the signalling mechanisms through which these cytokines induce their effects. Since the original discovery of the classical JAK (Janus activated kinase)–STAT (signal transducer and activator of transcription) pathway of signalling, it has become clear that the coordination and cooperation of multiple distinct signalling cascades — including the mitogen-activated protein kinase p38 cascade and the phosphatidylinositol 3-kinase cascade — are required for the generation of responses to interferons. It is anticipated that an increased understanding of the contributions of these recently identified pathways will advance our current thinking about how interferons work.
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Glossary
- HISTONE ACETYLTRANSFERASE
-
A protein that acetylates core histones, which results in important regulatory effects on chromatin structure and assembly, and on gene transcription.
- VIRAL CRK
-
(vCRK). The product of an oncogene encoded by the CT10 avian sarcoma virus. The oncogene transforms cells and can induce tumours in newborn chickens.
- SRC-HOMOLOGY-2 DOMAINS
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(SH2 domains). Protein domains that are commonly found in signal-transduction molecules. They specifically interact with phosphotyrosine-containing protein sequences.
- SH3 DOMAINS
-
(SRC-homology-3 domains). Protein domains that are commonly found in signal-transduction molecules. They specifically interact with certain proline-containing protein sequences. Classically, they contain either (Arg/Lys)-X-X-Pro-X-X-Pro or Pro-X-X-Pro-X-Arg motifs, where X denotes any amino acid.
- GUANINE-NUCLEOTIDE-EXCHANGE FACTORS
-
Proteins that stimulate the exchange of guanine diphosphate (GDP) for guanine triphoshate (GTP) in small GTPases, resulting in activation of the GTPase.
- BCR–ABL ONCOGENE
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A fusion gene that results from an abnormal chromosomal translocation in which the breakpoint-cluster region (BCR) is fused to the Abelson leukaemia virus (ABL) tyrosine-kinase gene. In humans, this oncogene is involved in the pathogenesis of chronic myeloid leukaemia and some cases of acute lymphoblastic leukaemia.
- CAP-DEPENDENT TRANSLATION
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An important step for the initiation of mRNA translation. It involves a complex process in which the Met-tRNAi initiator and the 40S and 60S ribosomal subunits are all assembled by eukaryotic translation-initiation factors into the 80S ribosome at the start codon of a specific mRNA.
- PLECKSTRIN-HOMOLOGY DOMAINS
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Amino-acid sequences that are present in several signalling proteins that mediate their function through binding phosphatidylinositols. A subset of these domains selectively binds phosphatidylinositol 3-kinase products. Pleckstrin-homology domains also anchor proteins to membranes by binding membrane lipids.
- PHOX-HOMOLOGY DOMAINS
-
Amino-acid sequences that are present in certain signalling proteins and that target these proteins to organelle membranes. Such targeting occurs through interactions between conserved motifs in the PHOX-homology domains and specific phosphoinositides. These domains have a structure that is distinct from pleckstrin-homology domains.
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Platanias, L. Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat Rev Immunol 5, 375–386 (2005). https://doi.org/10.1038/nri1604
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DOI: https://doi.org/10.1038/nri1604
