Recurrent Viral Capture of Cellular Phosphodiesterases that Antagonize OAS-RNase L

Abstract

Phosphodiesterases (PDEs) encoded by nidoviruses and rotaviruses (RVs) promote viral replication and pathogenesis. Putatively acquired by horizontal transfer of cellular PDE ancestor genes, viral PDEs inhibit the OAS-RNase L antiviral pathway, a key effector component of the innate immune response to dsRNA. Although the functional significance of these proteins is well-characterized, the evolutionary history of these proteins is less clear. We used phylogenetic approaches to identify at least five independent PDE acquisition events in viral evolutionary history. In addition, we assess that these PDE-encoding genes were horizontally transferred between coronavirus genera. Three viral clades withinNidovirales, merbecoviruses (MERS-CoV), embecoviruses (OC43), and toroviruses encode independently acquired PDEs, and a clade of rodent alphacoronaviruses acquired the embecovirus PDE via a relatively recent horizontal transfer event. Among rotaviruses, the Rotavirus A PDE was acquired independently from Rotavirus B and G PDEs, which share a common ancestor. Conserved motif analysis links all viral PDEs to a common ancestor among the mammalian AKAP7 proteins despite overall low levels of sequence conservation across these proteins. Additionally, we used ancestral sequence reconstruction and structural modeling to reveal that sequence and structural divergence are not well-correlated among these proteins. Specifically, merbecovirus PDEs are as structurally divergent from the ancestral protein and the solved human AKAP7 PDE structure as they are from each other. In contrast, comparisons of Rotavirus B and G PDEs reveal virtually unchanged structures despite evidence for loss of function in one, suggesting functionally significant changes that lie outside conserved catalytic sites. These findings highlight the complex and volatile evolutionary history of viral PDEs and provide a new framework to facilitate future studies on structural and sequence determinants of PDE function.

The nuclear matrix protein HNRNPU restricts hepatitis B virus transcription by promoting OAS3‐based activation of host innate immunity

“…29 The OAS/RNase L system is an innate immunity pathway that degrades viral and host mRNA to inhibit viral infections. 30 This study also revealed that OAS3 inhibits HBV transcription through the RNase L-dependent mechanism. Given that HNRNPU epigenetically regulates gene expression, 31 and our study demonstrated HNRNPU knockdown or overexpression resulted in a decrease or increase in OAS expression.…”

Birth of new protein folds and functions in the virome

“…Surprisingly, lineage C betacoronaviruses contain a distinct branch of PDEs (Fig. 4A) 47 . This suggests that there were two independent PDE acquisition events within the betacoronavirus genus, showing the strong selective pressure for betacoronaviruses to evade the OAS pathway.…”

Hidden evolutionary constraints dictate the retention of coronavirus accessory genes

“…The stability of these large genomes is facilitated by the incorporation of a proofreading exonuclease into the RNA polymerase complex, unique among RNA viruses, that enhances replication fidelity [11][12][13] . Consequently, coronaviruses can accommodate addition of genetic material in the form of accessory genes acquired via horizontal gene transfer [14][15][16] and gene duplication 6,17 .…”

“…The stability of these large genomes is facilitated by the innovation of a proofreading exonuclease into the RNA polymerase complex, unique among RNA viruses, that enhances replication fidelity [12][13][14] . Consequently, coronaviruses can accommodate addition of genetic material in the form of accessory genes acquired via horizontal gene transfer 8,15,16 and gene duplication 6,17 . Evolutionary theory on the streamlining of RNA virus genomes 1,3,4 predicts that accessory genes should encode near-immediate fitness benefits to avoid deletion.…”