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Review
. 2024 Jun 26;52(3):1393-1404.
doi: 10.1042/BST20231296.

A closer look at mammalian antiviral condensates

J Monty Watkins  1   2   3 , James M Burke  1   2
Affiliations
Review

A closer look at mammalian antiviral condensates

J Monty Watkins et al. Biochem Soc Trans. .

Abstract

Several biomolecular condensates assemble in mammalian cells in response to viral infection. The most studied of these are stress granules (SGs), which have been proposed to promote antiviral innate immune signaling pathways, including the RLR-MAVS, the protein kinase R (PKR), and the OAS-RNase L pathways. However, recent studies have demonstrated that SGs either negatively regulate or do not impact antiviral signaling. Instead, the SG-nucleating protein, G3BP1, may function to perturb viral RNA biology by condensing viral RNA into viral-aggregated RNA condensates, thus explaining why viruses often antagonize G3BP1 or hijack its RNA condensing function. However, a recently identified condensate, termed double-stranded RNA-induced foci, promotes the activation of the PKR and OAS-RNase L antiviral pathways. In addition, SG-like condensates known as an RNase L-induced bodies (RLBs) have been observed during many viral infections, including SARS-CoV-2 and several flaviviruses. RLBs may function in promoting decay of cellular and viral RNA, as well as promoting ribosome-associated signaling pathways. Herein, we review these recent advances in the field of antiviral biomolecular condensates, and we provide perspective on the role of canonical SGs and G3BP1 during the antiviral response.

Keywords: G3BP1; PKR; RNA; RNase L; condensate; stress granules.

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Conflict of interest statement

The authors declare that there are no competing interests associated with the manuscript.

Figures

Figure 1.
Figure 1.. Potential roles for SGs in regulating antiviral signaling.
Schematic of observed interactions between SGs (green), PRRs (yellow), and PAMPs (pink) and their effects on antiviral signaling. In model 1, SGs concentrate PAMPs and PRRs to promote antiviral signaling. In model 2, SGs sequester PRRs aways from PAMPs to dampen antiviral signaling. In model 3, SGs do not concentrate PRRs or PAMPs. SGs do not impact antiviral signaling, but instead are a consequence of antiviral signaling via the PKR pathway. Created with BioRender.com.
Figure 2.
Figure 2.. Viral-aggregated RNA condensates.
During infections that degrade host mRNAs, such as SARS-CoV-2 infection, G3BP1 can condense viral RNAs, leading to VARCs, which may disrupt viral replication by interfering with the viral replication organelle. Created with BioRender.com.
Figure 3.
Figure 3.. Double-stranded RNA-induced foci regulate the initiation of antiviral signaling.
Double stranded RNA-induced foci (dRIF) concentrate dsRNA-binding proteins including PKR, OAS3, and ADAR1. In addition, antiviral effectors such as RNase L also concentrate at dRIF. The assembly of dRIF correlates with the activation of the PKR and OAS-RNase L pathways. Created with BioRender.com.
Figure 4.
Figure 4.. Relationship between RNase L-induced bodies and stress granules.
Schematic of the SG and RLB assembly biogenesis pathways are displayed above a Venn diagram that illustrates the differences and similarities between the biogenesis, composition, and morphology of SGs and RLBs. Created with BioRender.com
Figure 5.
Figure 5.. RNase L-induced bodies concentrate RNase L-cleaved host and viral RNA.
Activation of the OAS-RNase L pathway leads to RNase L cleaving host mRNAs and viral genomes/mRNAs. The cleavage fragments, particularly 3′-end fragments, concentrate into RNase L-induced bodies (RLBs). The sequestration subgenomic flavivirus RNAs (sfRNA) reduces the ability of sfRNAs to inhibit mRNA decay machinery in P-bodies. Because RNase L cleavage of RNA leads to phosphorylation of eIF2α, RLBs may be a sight of ribosome-mediated stress responses. Created with BioRender.com.
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