Evolution of Class I cytokine receptors

Abstract

Background: The Class I cytokine receptors have a wide range of actions, including a major role in the development and function of immune and blood cells. However, the evolution of the genes encoding them remains poorly understood. To address this we have used bioinformatics to analyze the Class I receptor repertoire in sea squirt (Ciona intestinalis) and zebrafish (Danio rerio).

Results: Only two Class I receptors were identified in sea squirt, one with homology to the archetypal GP130 receptor, and the other with high conservation with the divergent orphan receptor CLF-3. In contrast, 36 Class I cytokine receptors were present in zebrafish, including representative members for each of the five structural groups found in mammals. This allowed the identification of 27 core receptors belonging to the last common ancestor of teleosts and mammals.

Conclusion: This study suggests that the majority of diversification of this receptor family occurred after the divergence of urochordates and vertebrates approximately 794 million years ago (MYA), but before the divergence of ray-finned from lobe-finned fishes around 476 MYA. Since then, only relatively limited lineage-specific diversification within the different Class I receptor structural groups has occurred.

Figure 1

Human Class I receptor chains and complexes. a) Topological representation of the five structural groups of Class I receptor chains adapted from Boulay et al, 2003 [10]. Depicted are the Immunoglobulin-like (Ig) domains, Cytokine receptor Homology Domains (CHDs), including conserved cysteines (thin bands) and WSXWS motifs (thick band), Fibronectin type III (FBN) domains, Transmembrane (TM) regions, and Intracellular Homology Region (IHR) sequences. Full receptor names can be found in the list of abbreviations. b) Assembly of Class I receptor chains into functional receptor complexes. Individual receptor chains form either homodimers or various heterocomplexes that bind to specific ligands. For receptor complexes that bind to multiple cytokines, only one receptor complex is listed. Although constituents of receptor complexes of the IL-2R functional family, the IL-2Rα and IL-15Rα receptor chains are not members of the Class I family of receptors, but instead contain distinctive 'sushi domain' structures [55]. The orphan receptor chain CLF-3 was not included as its arrangement into a receptor complex is yet to be established.

Figure 2

Sea squirt Class I receptor chains. a-b) Sequence alignments. Shown are alignments of the CHD of human (hs) and seasquirt (ci) GP130 (a) and CLF-3 (b) related sequences, with key residues annotated. c) Phylogenetic analysis of sea squirt receptors with representative sequences from each structural group of mammalian receptors and the two fruit fly dome receptors, using the Neighbourhood-Joining algorithm. Bootstrap values are indicated on branches as a percentage of 1000 replicates. d) Splice-site analysis. Schematic representation of the splice structure for the CHD of the above sequences in comparison to the fruit fly (dm) dome. Exons indicated with thick lines and introns with thin connecting lines. Specific residues indicated by standard one letter code.

Figure 3

Phylogenetic analysis of zebrafish Class I receptor chains. Phylogenetic trees were created for each of the five structural groups of Class I receptor chains with sequences from zebrafish (dr) along with those from human (hs) and mouse (mm): Group 1 (a), Group 2 (b), Group 3 (c), Group 4 (d). Trees were calculated on the basis of multiple alignments of the CHD domains (Additional files 4, 5, 6, 7).

Figure 5

Conservation of crucial intracellular motifs in zebrafish Class I receptor chains. Multiple sequence alignments of the intracellular regions of homologues of GP130 (a), LIFR and OSMR (b), and IL-7Rα (c) from zebrafish, human and mouse. The solid lines above the alignments indicate key regions of conservation: Box 1, Box 2, Box 3, serine rich (SR), and the internalization motifs. The dashed line under the consensus sequence represents conserved docking sites for the signaling molecules SHP-2/Socs3, Stat3, and Stat5.

Figure 6

Evolution of Class I cytokine receptors. Class I cytokine receptors are depicted as in Figure 1. The rounded rectangles display all Class I cytokine receptors identified from fruit fly, mosquito, sea squirt, zebrafish, and humans. The bolded rectangles represent the hypothetical receptors present at the time of divergence of protostomes from deuterostomes, urochordates from vertebrates, and ray-finned from lobe-finned fishes, respectively. The vertebrate Class I receptor chains have been further divided into structural groups as described, with the exception of CLF-3 that has been considered separately on the basis of its distinct evolutionary history. Estimation of the times of the key evolutionary events, expressed in millions of years ago (MYA), are based on molecular genomic approaches [56]. Arrows represent presumed evolutionary relationships.

Figure 4

Phylogenetic analysis of zebrafish Class I receptor chains. A phylogenetic tree was created for structural Group 5 of Class I receptor chains with sequences from zebrafish (dr) along with those from human (hs) and mouse (mm). Trees were calculated on the basis of multiple alignments of the CHD domains (Additional file 8).