Research article
Diversifying selection and functional analysis of interleukin-4 suggests antagonism-driven evolution at receptor-binding interfaces
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* Corresponding authors: Harmit S Malik hsmalik@fhcrc.org - Mark Bix mark.bix@stjude.org
1 Department of Immunology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105 USA
2 Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, PO Box 19024, WA 98109 USA
3 HHMI, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, PO Box 19024, WA 98109 USA
4 Division of Viral Immunology, Center for Aids Research, Kumamoto University, 2-2-1, Honjo, Kumamoto 860-0811 Japan
5 Institute for Systems Biology, 1441 North 34th Street, Seattle, WA 98103 USA
6 Trubion Pharmaceuticals, 2401 4th Ave, Seattle, WA 98121 USA
BMC Evolutionary Biology 2010, 10:223 doi:10.1186/1471-2148-10-223
Published: 22 July 2010Abstract
Background
Interleukin-4 (IL4) is a secreted immunoregulatory cytokine critically involved in host protection from parasitic helminths [1]. Reasoning that helminths may have evolved mechanisms to antagonize IL4 to maximize their dispersal, we explored mammalian IL4 evolution.
Results
This analysis revealed evidence of diversifying selection at 15 residues, clustered in epitopes responsible for IL4 binding to its Type I and Type II receptors. Such a striking signature of selective pressure suggested either recurrent episodes of pathogen antagonism or ligand/receptor co-evolution. To test the latter possibility, we performed detailed functional analysis of IL4 allotypes expressed by Mus musculus musculus and Mus musculus castaneus, which happen to differ at 5 residues (including three at positively selected sites) in and adjacent to the site 1 epitope that binds the IL4Rα subunit shared by the Type I and Type II IL4 receptors. We show that this intra-species variation affects the ability of IL4 neither to bind IL4 receptor alpha (IL4Rα) nor to signal biological responses through its Type I receptor.
Conclusions
Our results -- reminiscent of clustered positively selected sites revealing functionally important residues at host-virus interaction interfaces -- are consistent with IL4 having evolved to avoid recurrent pathogen antagonism, while maintaining the capacity to bind and signal through its cognate receptor. This work exposes what may be a general feature of evolutionary conflicts fought by pathogen antagonists at host protein-protein interaction interfaces involved in immune signaling: the emergence of receptor-binding ligand epitopes capable of buffering amino acid variation.