Origin and development of oligoadenylate synthetase immune system

Jiaxiang Hu, Xiaoxue Wang, Xing Yanling , Rong Enguang , Mengfei Ning, Jacqueline Smith, Yinhua Huang

Research output: Contribution to journalArticlepeer-review


Background: 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. 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.
Results: Ancient 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.
Conclusions: We 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.
Original languageEnglish
Article number201
Number of pages13
JournalBMC Evolutionary Biology
Publication statusPublished - 27 Dec 2018


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