title: Evolution of a Novel Antiviral Immune-Signaling Interaction by Partial-Gene Duplication.
abstract: 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.
authors.affiliation: Department of Microbiology and Cell Science, Institute of Food and Agricultural Sciences, University of Florida, Gainesville, FL, United States of America.
authors.forename: Bryan
authors.initials: B
authors.lastname: Korithoski
authors.affiliation: Department of Microbiology and Cell Science, Institute of Food and Agricultural Sciences, University of Florida, Gainesville, FL, United States of America.
authors.forename: Oralia
authors.initials: O
authors.lastname: Kolaczkowski
authors.affiliation: Whitney Laboratory for Marine Bioscience, University of Florida, St. Augustine, FL, United States of America.
authors.forename: Krishanu
authors.initials: K
authors.lastname: Mukherjee
authors.affiliation: Department of Microbiology and Cell Science, Institute of Food and Agricultural Sciences, University of Florida, Gainesville, FL, United States of America; Department of Food Science and Human Nutrition, University of Florida, Gainesville, FL, United States of America.
authors.forename: Reema
authors.initials: R
authors.lastname: Kola
authors.affiliation: Department of Biology, University of Florida, Gainesville, FL, United States of America.
authors.forename: Chandra
authors.initials: C
authors.lastname: Earl
authors.affiliation: Department of Microbiology and Cell Science, Institute of Food and Agricultural Sciences, University of Florida, Gainesville, FL, United States of America.
authors.forename: Bryan
authors.initials: B
authors.lastname: Kolaczkowski
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism*; D053468:CARD Signaling Adaptor Proteins / Q000737:chemistry / Q000378:metabolism*; D019143:Evolution, Molecular; D020440:Gene Duplication; D006801:Humans; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D053468:CARD Signaling Adaptor Proteins; D025801:Ubiquitin