Molecular Mechanisms for the Adaptive Switching Between the OAS/RNase L and OASL/RIG-I Pathways in Birds and Mammals

Abstract

Host cells develop the OAS/RNase L [2′–5′–oligoadenylate synthetase (OAS)/ribonuclease L] system to degrade cellular and viral RNA, and/or the OASL/RIG-I (2′–5′–OAS like/retinoic acid inducible protein I) system to enhance RIG-I-mediated IFN induction, thus providing the first line of defense against viral infection. The 2′–5′–OAS-like (OASL) protein may activate the OAS/RNase L system using its typical OAS-like domain (OLD) or mimic the K63-linked pUb to enhance antiviral activity of the OASL/RIG-I system using its two tandem ubiquitin-like domains (UBLs). We first describe that divergent avian (duck and ostrich) OASL inhibit the replication of a broad range of RNA viruses by activating and magnifying the OAS/RNase L pathway in a UBL-dependent manner. This is in sharp contrast to mammalian enzymatic OASL, which activates and magnifies the OAS/RNase L pathway in a UBL-independent manner, similar to 2′–5′–oligoadenylate synthetase 1 (OAS1). We further show that both avian and mammalian OASL can reversibly exchange to activate and magnify the OAS/RNase L and OASL/RIG-I system by introducing only three key residues, suggesting that ancient OASL possess 2–5A [px5′A(2′p5′A)n; x = 1-3; n ≥ 2] activity and has functionally switched to the OASL/RIG-I pathway recently. Our findings indicate the molecular mechanisms involved in the switching of avian and mammalian OASL molecules to activate and enhance the OAS/RNase L and OASL/RIG-I pathways in response to infection by RNA viruses.

Genetic responses of inbred chicken lines illustrate importance of eIF2 family and immune-related genes in resistance to Newcastle disease virus

“…In chickens, OAS has been shown to be encoded by only one gene (OASL) 37 and to be upregulated after infection with different viruses 38,39 including NDV 3,4,21 . The role of OASL in the control of NDV replication was confirmed in vitro 8 , as the overexpression of OASL reduced the replication of NDV and the absence of OASL significantly enhanced viral replication. In our study, OASL was upregulated by NDV challenge in Leghorns at 2 dpi.…”

Avian Pattern Recognition Receptor Sensing and Signaling

“…Although mouse Oasl1 also lacks NTase activity, mouse Oasl2, unlike human OASL, contains two critical aspartic acidresidues in its active site and exhibits OAS enzyme activity [136]. OASL displays antiviral activity against RNA viruses through its C-terminal UBL domain [137]. Upon initial viral infection and OASL induction as an ISG in response to IFN signaling, OASL bound to RIG-I and mimicked K63-linked ubiquitin [137].…”

“…OASL displays antiviral activity against RNA viruses through its C-terminal UBL domain [137]. Upon initial viral infection and OASL induction as an ISG in response to IFN signaling, OASL bound to RIG-I and mimicked K63-linked ubiquitin [137]. Typically, RIG-I activation requires dsRNA ligand and K63-linked ubiquitination by RIPLET to undergo intra filament and inter filament bridging.…”

“…Typically, RIG-I activation requires dsRNA ligand and K63-linked ubiquitination by RIPLET to undergo intra filament and inter filament bridging. OASL-mediated activation of RIG-I is more sensitive in that RIG-I requires only dsRNA ligand for its activation [137]. Recently, OASL was found to negatively regulate cGAS-STING signaling and type I IFN production upon dsDNA virus infection [138].…”

“…Chicken, duck, and goose OASL share similar domain organization, as described above. However, functional characterization indicated that avian OASL has accrued species-specific adaptations and functional divergence compared to their mammalian counterparts [137]. For instance, unlike mammalian OASL (human OASL and Oasl2), duck OASL binds dsRNA with an enhanced affinity and activates RNase L system in a UBL-dependent manner [137].…”