dsRNA-induced condensation of antiviral proteins modulates PKR activity

Corbet, Giulia; Bublitz, Gaia R.; Tay, Jian Wei; Parker, Roy

doi:10.1073/pnas.2204235119

Cited by 25 publications

(38 citation statements)

References 60 publications

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“…5H ) Thus, A3B has a critical function in regulating PKR during infection with different types of RNA viruses. Finally, we asked whether A3B impacts PKR-dsRNA condensates that are formed when dsRNAs are present in the cytoplasm 80 , 81 . We transfected cells with poly(I:C)-FITC to monitor PKR colocalization with dsRNAs and we confirmed that PKR formed large foci that are associated with poly(I:C) (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

APOBEC3B drives PKR-mediated translation shutdown and protects stress granules in response to viral infection

Manjunath

Ortega

et al. 2023

Nat Commun

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Double-stranded RNA produced during viral replication and transcription activates both protein kinase R (PKR) and ribonuclease L (RNase L), which limits viral gene expression and replication through host shutoff of translation. In this study, we find that APOBEC3B forms a complex with PABPC1 to stimulate PKR and counterbalances the PKR-suppressing activity of ADAR1 in response to infection by many types of viruses. This leads to translational blockage and the formation of stress granules. Furthermore, we show that APOBEC3B localizes to stress granules through the interaction with PABPC1. APOBEC3B facilitates the formation of protein-RNA condensates with stress granule assembly factor (G3BP1) by protecting mRNA associated with stress granules from RNAse L-induced RNA cleavage during viral infection. These results not only reveal that APOBEC3B is a key regulator of different steps of the innate immune response throughout viral infection but also highlight an alternative mechanism by which APOBEC3B can impact virus replication without editing viral genomes.

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Section: Resultsmentioning

confidence: 99%

APOBEC3B drives PKR-mediated translation shutdown and protects stress granules in response to viral infection

Manjunath

Ortega

et al. 2023

Nat Commun

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“…However, their function remains unknown. Although antiviral proteins do not typically localize to RLBs (e.g., PKR) (Corbet, Burke, Bublitz, & Parker, 2022), current efforts are underway to determine whether additional antiviral factors localize to RLBs and whether RLBs play a role in antiviral signaling. To assess the specific function of RLBs during the OAS/RNase L response, it will be necessary to perturb RLB assembly during RNase L‐mediated RNA decay.…”

Section: Discussionmentioning

confidence: 99%

Regulation of ribonucleoprotein condensates by RNase L during viral infection

Burke

2022

WIREs RNA

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In response to viral infection, mammalian cells activate several innate immune pathways to antagonize viral gene expression. Upon recognition of viral double-stranded RNA, protein kinase R (PKR) phosphorylates the alpha subunit of eukaryotic initiation factor 2 (eIF2α) on serine 51. This inhibits canonical translation initiation, which broadly antagonizes viral protein synthesis. It also promotes the assembly of cytoplasmic ribonucleoprotein complexes termed stress granules (SGs). SGs are widely thought to promote cell survival and antiviral signaling. However, co-activation of the OAS/RNase L antiviral pathway inhibits the assembly of SGs and promotes the assembly of an alternative ribonucleoprotein complex termed an RNase L-dependent body (RLB). The formation of RLBs has been observed in response to double-stranded RNA, dengue virus infection, or SARS-CoV-2 infection. Herein, we review the distinct biogenesis pathways and properties of SGs and RLBs, and we provide perspective on their potential functions during the antiviral response.

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“…This suggests that NLRP6 condensation may be an inherent property of NLRP6 and is not strictly dependent on dsRNA. Moreover, the formation of NLRP6 condensates may be limited to certain cell types since NLRP6 condensation with dsRNA was not observed in A549 cells transfected with poly(I:C) (Corbet et al , 2022). Finally, as with all proteins that form condensates, it is difficult to distinguish between disruptions in the protein's function generally, and the protein's function specifically within a condensate.…”

Section: Pattern Recognition Receptors Detect Foreign Nucleic Acidmentioning

confidence: 99%

“…First, PKR's substrate eIF2α is not enriched in dRIFs, implying that PKR in dRIFs would be unable to phosphorylate eIF2α (Zappa et al , 2022). However, other work suggests that eIF2α is not excluded from dRIFs and therefore may be available for phosphorylation by PKR found in dRIFs (Corbet et al , 2022). Second, point mutations reducing PKR‐PKR interactions and reduced PKR recruitment to dRIFs show enhanced phosphorylation of eIF2α prior to, and in response to, exogenous dsRNA (Zappa et al , 2022), suggesting that less PKR in dRIFs results in increased PKR signaling.…”

Section: Pattern Recognition Receptors Detect Foreign Nucleic Acidmentioning

confidence: 99%

“…Recently, several studies have shown that many of the nucleic acid PRRs, including PKR, cGAS, NLRP6, and NLRP1 assemble into discrete cytosolic condensates with their cognate nucleic acid substrates (Du & Chen, 2018; Shen et al , 2021; Corbet et al , 2022; Zappa et al , 2022). Critical issues in each of these assemblies are as follows: (i) what molecular interactions drive condensate formation?…”

Section: Pattern Recognition Receptors Detect Foreign Nucleic Acidmentioning

confidence: 99%

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Nucleic acid–protein condensates in innate immune signaling

Corbet

Parker

2022

The EMBO Journal

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The presence of foreign nucleic acids in the cytosol is a marker of infection. Cells have sensors, also known as pattern recognition receptors (PRRs), in the cytosol that detect foreign nucleic acid and initiate an innate immune response. Recent studies have reported the condensation of multiple PRRs including PKR, NLRP6, and cGAS, with their nucleic acid activators into discrete nucleoprotein assemblies. Nucleic acid–protein condensates form due to multivalent interactions and can create high local concentrations of components. The formation of PRR‐containing condensates may alter the magnitude or timing of PRR activation. In addition, unique condensates form following RNase L activation or during paracrine signaling from virally infected cells that may play roles in antiviral defense. These observations suggest that condensate formation may be a conserved mechanism that cells use to regulate activation of the innate immune response and open an avenue for further investigation into the composition and function of these condensates. Here we review the nucleic acid–protein granules that are implicated in the innate immune response, discuss general consequences of condensate formation and signal transduction, as well as what outstanding questions remain.

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dsRNA-induced condensation of antiviral proteins modulates PKR activity

Cited by 25 publications

References 60 publications

APOBEC3B drives PKR-mediated translation shutdown and protects stress granules in response to viral infection

APOBEC3B drives PKR-mediated translation shutdown and protects stress granules in response to viral infection

Regulation of ribonucleoprotein condensates by RNase L during viral infection

Nucleic acid–protein condensates in innate immune signaling

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