Recurrent Loss-of-Function Mutations Reveal Costs to OAS1 Antiviral Activity in Primates

Abstract

SUMMARY Immune responses counteract infections but also cause collateral damage to hosts. Oligoadenylate Synthetase 1 (OAS1) binds double-stranded RNA from invading viruses, and produces 2′–5′ linked oligoadenylate (2–5A) to activate Ribonuclease L (RNase L), which cleaves RNA to inhibit virus replication. OAS1 can also undergo autoactivation by host RNAs, a potential trade-off to antiviral activity. We investigated functional variation in primate OAS1 as a model for how immune pathways evolve to mitigate costs and observed a surprising frequency of loss-of-function variation. In gorillas, we identified a polymorphism that severely decreases catalytic function, mirroring a common variant in humans that impairs 2–5A synthesis through alternative splicing. OAS1 loss-of-function variation is also common in monkeys, including complete loss of 2–5A synthesis in tamarins. The frequency of loss-of-function alleles suggests that costs associated with OAS1 activation can be so detrimental to host fitness that pathogen-protective effects are repeatedly forfeited.

Characteristics of Human OAS1 Isoform Proteins

“…The p42, p44, p46, p48 and p52 hOAS1 proteins were previously shown to have 2-5A synthetase activity [14,21,22]. Consistent with our data, a recent study that directly compared the relative activities of partially purified p42, p44, p46, p48 and p52 expressed in E. coli as maltose-binding protein (MBP) fusion proteins, found that all of the isoforms were able to robustly synthesize 2-5A [23]. However, at low concentrations, the p44 and p52 isoforms had lower activities than the other isoforms.…”

“…The p42 and p46 isoforms were expressed at much higher levels than the p44, p48 and p52 isoforms ( Figure 3A). It was previously shown that hOAS1 p42 or p46 proteins were expressed in yeast at higher levels than p44, p48 or p52 [23]. In another study, although the transcript levels for Xpress tagged p42, p44, p46 and p48 were equivalent in HEK 293T cells after 48 h of expression, p44 and p48 had impaired protein expression compared to p42 and p46.…”

RNA regulation of the antiviral protein 2′‐5′‐oligoadenylate synthetase

“…Human OASL is nonetheless an important part of innate immunity and is thought to have evolved to exert its antiviral effect by binding RIG-I and enhancing its signaling (Ibsen et al, 2015;Zhu et al, 2014). Loss-of-function mutations in primate OAS1 have also been identified that substantially impair 2-5A synthesis or completely eliminate enzymatic activity altogether (Carey et al, 2019). Such species-specific differences in the OAS family presumably have their origins, at least in part, in the distinct viral challenges experienced by each species as well as the associated evolutionary "arms race" between host immune defense and viral countermeasure.…”

Alternative splicing coupled with transcript degradation modulates OAS1g antiviral activity

“…Further, this increased 58 expression of Oas1g improves the ability of macrophages that lack the unproductive splice site to 59 withstand infection by encephalomyocarditis virus (EMCV). However, removal of the Oas1g 60 alternative splice site also leads to an increase in apoptotic cell death in uninfected cells, a finding 61 consistent with the idea that activation of the 2-5A anti-viral system can be detrimental to host fitness 62 (Zhou et al 1997;Andersen et al 2007;Carey et al 2019). Beyond Oas1g, we find AS-NMD events 63 in a number of other crucial innate immune response transcripts, suggesting this is a common 64 mechanism of mitigation for responses that might otherwise be unchecked or inappropriately scaled.…”

“…Carey 224 et al 2019;Kjaer et al 2009). This is exemplified by the surprisingly high frequency of loss-of-225 function mutations in Oas1 in primates(Carey et al 2019), and the fact that OAS1 activity has been 226 completely lost in several animal lineages, including teleost fish and insects(Kjaer et al 2009). 227Moreover, while mice deficient for RNase L, the downstream effector of Oas1 in the 2-5A system, 228 exhibit susceptibility to viral infection(Zhou et al 1997), in the absence of infection they display 229 significantly increased longevity(Andersen et al 2007).…”