Evolution of a Novel Antiviral Immune-Signaling Interaction by Partial-Gene Duplication

• Published in: PloS one Vol. 10; no. 9; p. e0137276
• Main Authors: Korithoski, Bryan, Kolaczkowski, Oralia, Mukherjee, Krishanu, Kola, Reema, Earl, Chandra, Kolaczkowski, Bryan
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 10.09.2015; Public Library of Science (PLoS)
• Subjects: Amino acids; Analysis; Animals; Antiviral agents; Antiviral Agents - metabolism; Antiviral drugs; Bioinformatics; CARD Signaling Adaptor Proteins - chemistry; CARD Signaling Adaptor Proteins - metabolism; Caspase; Clustering; Coevolution; Complications and side effects; Cytoplasm; Differentiation; Dosage and administration; Evolution; Evolution, Molecular; Food; Gene clusters; Gene Duplication; Genetic aspects; Genomes; Homology; Humans; Immune response; Immune response (cell-mediated); Immunomodulation; Molecular biology; Molecular Docking Simulation; Phylogenetics; Physiological aspects; Protein Binding; Protein interaction; Protein Structure, Tertiary; Protein-protein interactions; Proteins; Receptors; Recruitment; Reproduction (copying); Ribonucleic acid; RNA; Science; Signal Transduction; Signaling; Ubiquitin; Ubiquitin - metabolism; United States; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0137276

The RIG-like receptors (RLRs) are related proteins that identify viral RNA in the cytoplasm and activate cellular immune responses, primarily through direct protein-protein interactions with the signal transducer, IPS1. Although it has been well established that the RLRs, RIG-I and MDA5, activate IPS1 through binding between the twin caspase activation and recruitment domains (CARDs) on the RLR and a homologous CARD on IPS1, it is less clear which specific RLR CARD(s) are required for this interaction, and almost nothing is known about how the RLR-IPS1 interaction evolved. In contrast to what has been observed in the presence of immune-modulating K63-linked polyubiquitin, here we show that-in the absence of ubiquitin-it is the first CARD domain of human RIG-I and MDA5 (CARD1) that binds directly to IPS1 CARD, and not the second (CARD2). Although the RLRs originated in the earliest animals, both the IPS1 gene and the twin-CARD domain architecture of RIG-I and MDA5 arose much later in the deuterostome lineage, probably through a series of tandem partial-gene duplication events facilitated by tight clustering of RLRs and IPS1 in the ancestral deuterostome genome. Functional differentiation of RIG-I CARD1 and CARD2 appears to have occurred early during this proliferation of RLR and related CARDs, potentially driven by adaptive coevolution between RIG-I CARD domains and IPS1 CARD. However, functional differentiation of MDA5 CARD1 and CARD2 occurred later. These results fit a general model in which duplications of protein-protein interaction domains into novel gene contexts could facilitate the expansion of signaling networks and suggest a potentially important role for functionally-linked gene clusters in generating novel immune-signaling pathways.