Interferonien evoluutiosta artikkeli , hyvä linkki (2017)

https://www.frontiersin.org/articles/10.3389/fimmu.2017.00209/full

Front. Immunol., 02 March 2017 | https://doi.org/10.3389/fimmu.2017.00209

Evolution of Interferons and Interferon Receptors

Chris J. Secombes* and Jun Zou

• Scottish Fish Immunology Research Centre, University of Aberdeen, Aberdeen, UK

PRR, pattern recogniotion receptors

IFN system 

IFN genes

IFN receptors

Signal molecules 

Antiviral response

ISG, IFN-stimulated genes

Sensors

TLR,Toll-like receptor ( Human: 13)

PAMPs,  pathogen associated molecular patterns 

 TLR1

TLR2

TLR3

TLR4, LPS sensor

TLR5, flagellin sensor

TLR

TLR7

TLR8

TLR9, CpG PAMP, microbial CpG DNA

TLR10

TLR11

TLR12

TLR13

Interferons

IFN alpha, Type I

IFN beta, Type I

IFN gamma,Type II

IFN lambda,Type III

Receptors

IFNAR1

IFNAR2

Regulation

 IRF, interferon regulatory factors 

 IRF3 and IRF7 are key regulators for initiation of IFN expression,

 IRF4 and IRF8 have opposite roles to inhibit or shutdown the IFN response when viruses are cleared from the host.

JAK, Jansu kianses 

STAT, Signal transducers and activators of transcription 

 JAKs, STAT1/2, and IRF9 are essential for IFN signaling,

PIAS, protein inhibitors of activated STAT 

SOCS, Suppressors of cytokine signaling
IFN signaling, negatively regulated by PIAS and SOCS.

IFN Gene Structure

 One of the benefits of intronless IFN genes is that they do not require RNA intron splicing for synthesizing functional proteins, hence saving time and energy and eliminating the RNA processing step, which could be targeted by viruses. However, whether this provides a selective advantage still needs to be determined.

The retrotransposition events appear to have had profound impacts on the evolution of type I IFN genes in vertebrates and raises many interesting questions. Such events also make it difficult to establish orthologous relationships when undertaking comparative analyses of functions between intron-containing fish/amphibian IFNs with their amniote counterparts. Intriguingly, the intron-containing and intronless type I IFN genes are regulated in a similar manner, governed by the activation of a panel of conserved PRRs (i.e., TLRs and RIG-I family) and IRFs (i.e., IRF3 and IRF7) (6, 7). For example, the binding sites of IRF3 and IRF7 are present in the promoter regions of both intron-containing and intronless type I IFN genes.

some mammals possess functional intronless type III genes, but they have not been expanded as much as seen for type I IFN genes.

Alternative Splicing

The presence of introns allows the potential for alternative splicing, and in some of the teleost type I IFN genes, this can occur at the 5′ end of the transcript (41, 42). This has been shown to generate intracellular forms of the type I IFN molecule that can elicit IFN signaling and induction of ISG expression via intracellular IFN receptors (29), as a unique means to combat viral infection. In rainbow trout, the recombinant proteins of the two intracellular forms of type I IFNs generated from a single IFN gene (belonging to the IFN-a subgroup) by alternative splicing have been shown to possess similar functions to the secreted IFN and are able to trigger Mx gene expression in a fibroblast cell line (RTG-2 cells) and protect cells against viral infection. In HEK293 cells with over-expressed intracellular type I IFN and its putative intracellular receptors, induced phosphorylation of STAT1 and STAT2 occurs, suggesting an intracellular IFN system mimicking the actions of secreted type I IFNs exists to be deployed for defending host cells against viral infection (29). Production of intracellular type I IFNs does not require secretion, hence reducing the time and energy for the synthesis in the infected cells, especially at the very early stage of infection, to establish an activated antiviral state. In addition, the intracellular IFN system could provide advantages for the host cells to avoid viral blocking of the IFN secretion pathway and interference of extracellular factors on activation of membrane receptors.

IFN Gene/Protein Diversity

 Multiple genes are commonly present for both type I and type III IFNs. In mammals the large number of type I IFN genes present can be grouped into subtypes, namely α, β, κ, ε, ω/τ, and δ/ζ. Large numbers of type I IFN genes are also present in teleost fish and amphibians, mainly of intronless forms in the latter case. Most of the encoded mammalian IFN proteins have four conserved cysteines (4C), but some possess only two cysteines (2C), as seen with IFN-β and IFN-ε. 4C-containing IFNs are also seen in fish (cartilaginous and bony), amphibians, reptiles, and birds and are thought to represent the ancestral form. Nevertheless, 2C forms of the IFN protein are also seen in cartilaginous and ray-finned bony fish (i.e., not in lobe-finned bony fish—coelacanth) and amphibians, but the pair of cysteines that is retained can differ (Figure 4). Thus, in mammals, amphibians, and cartilaginous fish, it is cysteine 2 and 4 that are retained, while in the 2C subgroups in ray-finned bony fish (holosteans and teleosts), it is cysteines 1 and 3 (20, 28). Interestingly, a recent teleost fish IFN subgroup (termed IFNh) has been described in several perciforme species that groups with the 2C clade but has six cysteines, two of which are aligned in the same position as those in the bony fish group I (2C) type I IFNs (43). Curiously, the perciforme IFNh proteins have an elongated region of approximately 20 aa at the C-terminus and possess similar antiviral functions to the perciforme IFNd previously reported (44, 45). In reptiles and birds only the 4C IFN proteins are known to date, supporting the concept that the 4C form was ancestral and that the 2C forms evolved independently in cartilaginous fish, ray-finned fish, amphibians, and mammals, in the latter two groups following retrotransposition events.

there is a single gene for IFN-γ in most vertebrate groups

 IFN Receptors

Six receptor molecules are known to interact with type I, II, and III IFNs in mammals. 

Although existing as multiple isoforms, type I IFNs bind to the same protein complex consisting of two subunits of the receptor chains IFNAR1 and IFNAR2.

 Similarly, the type II IFN (IFN-γ) signals through a receptor composed of IFN-γR1 and IFN-γR2, 

and all the type III IFNs share the same receptor complex of IFN-λR1 (IL-28R1) and IL-10R2.

 In mammals, all four fibronectin domains are shown to be involved in receptor binding. With only two such domains, how fish type I IFNs form a complex with the receptors is a mystery, especially as crystal structural analyses indicate that fish type I IFNs are structurally similar to that of their mammalian homologs, consisting of six α-helices (22).

 Interestingly, elephant shark also has two copies of the IFN-γR1 gene, which are tandemly arranged in the genome, one of which has a short intracellular region containing well-conserved binding motifs for JAK1 and STAT1. Whether these IFN-γ receptors are functional remains to be investigated.

Conclusion

We have learnt a lot about IFN and IFN receptor genes throughout the jawed vertebrate classes, in large part due to the sequencing of the genome of increasing numbers of species. While functional studies lag behind in many cases, studies in fish (especially teleosts) have demonstrated their important role in antiviral defense in early vertebrates as seen in mammals. It is clear that IFN genes have undergone extensive expansion in many lineages, in some cases associated with the generation of intronless genes following retrotransposition, and in other cases following WGD events. The protein cysteine pattern appears to define IFN types in most vertebrate classes, with loss of cysteine 1 and 3 having apparently occurred independently in cartilaginous fish, amphibians, and mammals. The loss of cysteines 2 and 4 in ray-finned fish appears unique and demonstrates the plasticity of the IFN molecule. It is likely a few surprises regarding IFN gene function in different vertebrate groups are still to be uncovered.

References....

Keywords: interferon, interferon receptor, evolution, retrotransposition, gene duplication, fish, vertebrate

Citation: Secombes CJ and Zou J (2017) Evolution of Interferons and Interferon Receptors. Front. Immunol. 8:209. doi: 10.3389/fimmu.2017.00209

Received: 19 December 2016; Accepted: 15 February 2017;
Published: 02 March 2017

Edited by:
Claudia U. Duerr, McGill University, Canada

Reviewed by:
Wenjun Liu, Institute of Microbiology (CAS), China
Philippe Georgel, University of Strasbourg, France