Type I interferon (IFN) responses are regulated by host, pathogen and environmental factors. These factors calibrate the host defences while limiting tissue damage and preventing autoimmunity.
Type I IFNs signal via the IFNα receptor (IFNAR) to activate receptor-associated Janus kinase 1 (JAK1) and tyrosine kinase 2 (TYK2) kinases and downstream signal transducer and activator of transcription (STAT) transcription factors; these transcription factors then induce the expression of IFN-stimulated genes (ISGs). Type I IFNs activate the IFN-stimulated gene factor 3 (ISGF3) complex, which is comprised of STAT1, STAT2 and IFN-regulatory factor 9 (IRF9); the ISGF3 complex binds to IFN-stimulated response elements (ISREs) to induce the expression of antiviral genes.
Type I IFN signalling is regulated in a quantitative and qualitative manner. The magnitude of signalling is increased by induction of STAT1 and IRF9 expression and amplification of JAK signalling by spleen tyrosine kinase (SYK) and protein tyrosine kinase 2 (PYK2). Conversely, the magnitude of signalling is decreased by suppressor of cytokine signalling (SOCS) and ubiquitin carboxy-terminal hydrolase 18 (USP18) proteins and by the downregulation and internalization of IFNAR. The qualitative nature of type I IFN responses is determined by the balance between the activation of various STATs and ISGF3.
Type I IFN-induced transcription is regulated by the post-translational modification of STATs, chromatin remodelling, the epigenetic landscape and cooperation with other transcription factors, co-activators and co-repressors.
ISGs encode proteins that regulate the translation of IFNAR and JAK–STAT signalling components and of ISGs themselves. Type I IFNs also induce the expression of microRNAs that regulate the IFN response.
Chronic type I IFN responses can promote autoimmunity by increasing antigen presentation, lymphocyte-mediated adaptive immune responses and chemokine expression. In chronic infections, type I IFNs can induce immunosuppression in part by increasing expression of interleukin-10 and programmed cell death 1 ligand 1 (PDL1).
Type I interferons (IFNs) activate intracellular antimicrobial programmes and influence the development of innate and adaptive immune responses. Canonical type I IFN signalling activates the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway, leading to transcription of IFN-stimulated genes (ISGs). Host, pathogen and environmental factors regulate the responses of cells to this signalling pathway and thus calibrate host defences while limiting tissue damage and preventing autoimmunity. Here, we summarize the signalling and epigenetic mechanisms that regulate type I IFN-induced STAT activation and ISG transcription and translation. These regulatory mechanisms determine the biological outcomes of type I IFN responses and whether pathogens are cleared effectively or chronic infection or autoimmune disease ensues.
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We thank P. Crow for critical review of the manuscript. This work was supported by grants from the US National Institutes of Health.
The authors declare no competing financial interests.
(miRNAs). Small RNA molecules that regulate the expression of genes by binding to the 3′ untranslated regions of specific mRNAs.
- Degron sequence
Degrons are signals within proteins that target them for rapid degradation. Degrons can be overt, as in the case of the N-end rule, or covert, as in the case of cyclins. For example, cyclin B must be rapidly destroyed after mitosis, and this is achieved by kinase-regulated access to a 'destruction box' sequence in cyclin B that stimulates polyubiquitylation and subsequent degradation by the proteasome.
A multiprotein complex that functions as a co-activator of transcription in all eukaryotes.
A sumoylated protein has undergone a type of post-translational protein modification in which the ubiquitin-like protein SUMO (small ubiquitin-related modifier) is covalently attached to the protein by an enzymatic cascade that is analogous to the cascade involved in protein ubiquitylation.
- CpG islands
Sequences of 0.5–2 kilobases that are rich in CpG dinucleotides. They are mostly located upstream of housekeeping genes and also of some tissue-specific genes. They are constitutively hypomethylated in many animal cell types.
- RVB proteins
ATP-binding proteins that belong to the ATPase- associated with diverse cellular activities (AAA) family of ATPases. They are found in different protein and nucleoprotein complexes that have roles in diverse cellular responses, including transcription, mitosis, development, apoptosis and DNA damage responses.
- IFN signature
A pattern of increased expression of interferon- stimulated genes (ISGs) in tissue samples or stimulated cells. The IFN signature is typically detected by using a high-throughput approach, such as microarray or RNA sequencing, to analyse gene expression.
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Ivashkiv, L., Donlin, L. Regulation of type I interferon responses. Nat Rev Immunol 14, 36–49 (2014). https://doi.org/10.1038/nri3581
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Granulocyte-macrophage colony-stimulating factor suppresses induction of type I interferon in infants with severe pneumonia
Pediatric Research (2023)
Engineering potent live attenuated coronavirus vaccines by targeted inactivation of the immune evasive viral deubiquitinase
Nature Communications (2023)
Inflammation and DNA damage: cause, effect or both
Nature Reviews Rheumatology (2023)
Emerging principles of cytokine pharmacology and therapeutics
Nature Reviews Drug Discovery (2023)