Evolution of MDA-5/RIG-I-dependent innate immunity: Independent evolution by domain grafting

Abstract

Interferons (IFNs) comprise a family of secreted proteins (cytokines) produced by cells following virus infection and create an antiviral state in neighboring cells (1-6). The relationship between IFN and viral infection is well documented and supported by studies employing neutralizing antibodies and IFN-receptor knockout mice, which document a direct role for IFN in mediating host defense against viruses (7,8). Moreover, IFNs are now recognized as multifunctional molecules that also provide defense against bacterial infection (especially intracellular parasites), induce antitumor activity (both direct and immune system-mediated), and stimulate or inhibit differentiation depending on cellular context (5, 9). In addition, type I IFNs also induce apoptosis of virus-infected cells and activate natural killer and T cells, thus activating the adaptive immune system as well (3).The expression of type I IFN is stringently regulated by the activation of pre-existing transcription factors, such as IFN regulatory factor 3 (IRF-3), NF-B, and ATF-2-c-Jun [supporting information (SI) Fig. S1] (10-12). These transcription factors are activated and, therefore, type I IFN is induced by bacterial components, such as lipopolysaccharide, and CpG DNA in leukocytes, such as macrophages and dendritic cells, as well as by viral infection (13,14). Targeted-gene-disruption studies indicate that Toll-like receptors (TLRs) recognize pathogenassociated molecular patterns. TLR3, TLR4, mouse TLR7 (human TLR8), and TLR9 function as signaling receptors for extracellular double-stranded RNA (dsRNA), lipopolysaccharide, viral single-stranded RNA, and CpG DNA, respectively (15-18). The interaction of these pathogen-associated molecular patterns with the extracellular leucine-rich repeat of the TLR facilitates the recruitment of adaptor molecules to the cytoplasmic Toll-IL-1 receptor domain of the TLR (19). The adaptors MyD88, IL-1 receptor associated kinase (IRAK), and TRAF6 are recruited by many TLRs and activate signaling cascades. For TLR7 and TLR9, type I IFN is induced by this MyD88-dependent pathway (19). TLR4 and TLR3 activate an additional signaling pathway called the MyD88-independent pathway, which recruits another adaptor molecule, Trif, and activates a second set of genes, including those of type I IFN, through activation of IRF-3 (20, 21). However, for most cell types, it has been postulated that the replication of viruses results in an accumulation of intracellular dsRNA, which triggers host response mechanisms that include expression of type I IFN (22). This signaling pathway is apparently distinct from that mediated by TLR3 and constitutes a major pathway activated by viral infection.Recent studies identified two proteins, melanoma differentiation associated gene-5 (MDA-5) and retinoic acid inducible gene I (RIG-I), as intracellular sensors of dsRNA responsible for induction of type I IFN (23, 24). Analysis of mda-5 or RIG-I knockout mice demonstrates that this TLR-independent pathway is central for innate immunity against viral ...

Structural basis for m7G recognition and 2′-O-methyl discrimination in capped RNAs by the innate immune receptor RIG-I

“…The 2′-O-methylation of 5′-end nucleotide is the essential modification to avoid recognition by RIG-I and residue H830 is the sensor for this modification on Cap-1 RNAs. RIG-I is found only in higher eukaryotes like humans and other vertebrates, and this coincides with the emergence of 2′-O-methyltransferases over the course of evolution (28). All human cellular mRNAs bear either Cap-1 or Cap-2 structures, and based on our findings such RNAs cannot activate RIG-I, regardless of single-stranded or double-stranded ends.…”

Fish virus-induced interferon exerts antiviral function through Stat1 pathway

“…In mammals, RIG-I and Mda5 are shown to preferentially sense dsRNA during RNA virus evasion, to elicit IFN antiviral response (Yoneyama and Fujita, 2009). These gene counterparts also exist in fish genome (Sarkar et al, 2008;Zhang et al, 2007;Zou et al, 2009). Actually, some important genes, including RIG-I, Mda5, MITA, TBK1, IRF3 and IRF7, which are known to play essential roles in virus-activated mammalian IFN response (Tamura et al, 2008), have been identified in crucian carp (Jiang et al, 2009;Zhang et al, 2003a;Zhang et al, 2007;Zhang et al, 2003b).…”

Mitochondrial Antiviral Signaling Protein Plays a Major Role in Induction of the Fish Innate Immune Response against RNA and DNA Viruses

“…Since fish express a typical MAVS involved in IFN production, they should also possess specific sensors of the RLR pathways that would be counterparts of mammalian RIG-I and MDA5. A recent survey of sequences sharing the MDA-5 and RIG-I domain arrangement (CARD1-CARD2-helicase-DEAD/DEAH) revealed that fish possess likely counterparts of MDA5 but not RIG-I, suggesting that the complete RLR pathway may have originated recently in the tetrapod or even the mammalian lineage (30). Combining in silico analysis and RACE, we identified a fish transcript encoding a protein most similar to RIG-I, with two CARDs and a helicase motif.…”

“…Concerning the RLRs, sequence data present in GenBank suggest that fish also possess RIG-I-like molecules and several of the downstream signaling molecules found in mammals. A recent extensive study of RLR evolution concluded that orthologs of MDA5, but not RIG-I, were found in fish, suggesting that MDA5 appeared before RIG-I in vertebrate evolution (30). In the present study, we cloned MAVS-like cDNAs from several fish species (including salmon and zebrafish) and showed that they were true orthologs of mammalian MAVS.…”