Abstract
BackgroundOligoadenylate synthetases (OASs) are widely distributed in Metazoa including sponges, fish, reptiles, birds and mammals and show large variation, with one to twelve members in any given species. Upon double-stranded RNA (dsRNA) binding, avian and mammalian OASs generate the second messenger 2'-5'-linked oligoadenylate (2-5A), which activates ribonuclease L (RNaseL) and blocks viral replication. However, how Metazoa shape their OAS repertoires to keep evolutionary balance to virus infection is largely unknown. We performed comprehensive phylogenetic and functional analyses of OAS genes from evolutionarily lower to higher Metazoa to demonstrate how the OAS repertoires have developed anti-viral activity and diversified their functions.ResultsAncient Metazoa harbor OAS genes, but lack both upstream and downstream genes of the OAS-related pathways, indicating that ancient OASs are not interferon-induced genes involved in the innate immune system. Compared to OASs of ancient Metazoa (i.e. sponge), the corresponding ones of higher Metazoa present an increasing number of basic residues on the OAS/dsRNA interaction interface. Such an increase of basic residues might improve their binding affinity to dsRNA. Moreover, mutations of functional residues in the active pocket might lead to the fact that higher Metazoan OASs lose the ability to produce 3'-5'-linked oligoadenylate (3-5A) and turn into specific 2-5A synthetases. In addition, we found that multiple rounds of gene duplication and domain coupling events occurred in the OAS family and mutations at functionally critical sites were observed in most new OAS members.ConclusionsWe propose a model for the expansion of OAS members and provide comprehensive evidence of subsequent neo-functionalization and sub-functionalization. Our observations lay the foundation for interrogating the evolutionary transition of ancient OAS genes to host defense genes and provide important information for exploring the unknown function of the OAS gene family.
Highlights
Oligoadenylate synthetases (OASs) are widely distributed in Metazoa including sponges, fish, reptiles, birds and mammals and show large variation, with one to twelve members in any given species
To infer whether the OAS/ribonuclease L (RNaseL) pathway in higher animals is present in lower Metazoa, we searched for seven genes related to the OAS/RNaseL pathway, including OAS, IFN, Interferon receptor (IFNR), Janus kinase (JAK), Signal transducer and activator of transcription 1/2 (STAT1/2) and RNaseL in four sponge species
Eight lower Metazoa (Acropora coral, Acropora digitifera; Starlet sea anemone, Nematostella vectensis; Mountainous star coral, Orbicella faveolata; Springtails, Orchesella cincta; Pacific oyster, Crassostrea gigas; Owl limpet, Lottia gigantea; Lamp shell, Lingula anatina; and Acorn worm, Saccoglossus kowalevskii) contain the OAS gene, but do not harbor STAT1/2, IFN, IFNR or RNaseL genes (Table 1). This indicates that the OAS/RNaseL anti-viral pathway does not exist in lower Metazoa (Fig. 1)
Summary
Oligoadenylate synthetases (OASs) are widely distributed in Metazoa including sponges, fish, reptiles, birds and mammals and show large variation, with one to twelve members in any given species. Upon doublestranded RNA (dsRNA) binding, avian and mammalian OASs generate the second messenger 2'-5'-linked oligoadenylate (2-5A), which activates ribonuclease L (RNaseL) and blocks viral replication. Oligoadenylate synthetases (OASs) are dsRNA sensors distributed widely in Metazoa. The OAS repertoires show large variation, where one, four and twelve OAS members have been identified in birds, primates and rodents respectively [1,2,3]. Expression of OAS genes is up-regulated during infections of a wide spectrum of RNA viruses, such as human immunodeficiency virus (HIV) [5] and influenza A virus [6]. Trimers or higher oligomers can serve as unique second messengers to activate ribonuclease L (RNaseL) and induce RNA degradation [9]
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