Inhibition of PKR by Viruses

Cesaro, Teresa; Michiels, Thomas

doi:10.3389/fmicb.2021.757238

Cited by 56 publications

(43 citation statements)

References 133 publications

(163 reference statements)

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“…The formation of dRIFs has implications for the activation of PKR in a number of biological contexts. We anticipate that dRIFs may be important for PKR activation in some viral infections since viruses use multiple mechanisms to limit PKR activation (reviewed in Cesaro and Michiels [ 52 ]). For example, hepatitis C virus blocks PKR dimerization through the NS5A protein ( 53 , 54 ).…”

Section: Discussionmentioning

confidence: 99%

dsRNA-induced condensation of antiviral proteins modulates PKR activity

Corbet

Bublitz

Tay³

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Mammalian cells respond to dsRNA in multiple manners. One key response to dsRNA is the activation of PKR, an eIF2α kinase, which triggers translational arrest and the formation of stress granules. However, the process of PKR activation in cells is not fully understood. In response to increased endogenous or exogenous dsRNA, we observed that PKR forms novel cytosolic condensates, referred to as dsRNA-induced foci (dRIFs). dRIFs contain dsRNA, form in proportion to dsRNA, and are enhanced by longer dsRNAs. dRIFs enrich several other dsRNA-binding proteins, including ADAR1, Stau1, NLRP1, and PACT. Strikingly, dRIFs correlate with and form before translation repression by PKR and localize to regions of cells where PKR activation is initiated. We hypothesize that dRIF formation is a mechanism that cells use to enhance the sensitivity of PKR activation in response to low levels of dsRNA or to overcome viral inhibitors of PKR activation.

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Section: Discussionmentioning

confidence: 99%

dsRNA-induced condensation of antiviral proteins modulates PKR activity

Corbet

Bublitz

Tay³

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…In particular, previous studies have shown that stress granules can suppress viral replication and function as a key part of the antiviral host response to various viral pathogens ( Onomoto et al, 2012 ; McCormick and Khaperskyy, 2017 ). Stress granule formation in virus-infected cells is initiated when double-stranded (ds)RNA or single-stranded (ss)RNA, common viral replication intermediates, bind to protein kinase R (PKR), triggering its autophosphorylation and activation ( Cesaro and Michiels, 2021 ). Once activated, PKR phosphorylates the eukaryotic translation initiation factor (eIF2α) and triggers assembly of stress granules by the nucleating proteins Ras-GTPase-activating SH3-domain-binding protein 1 (G3BP1) and T-cell-restricted intracellular antigen-1 (TIA-1) ( Gilks et al, 2004 ; Matsuki et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Differential effect of SARS-CoV-2 infection on stress granule formation in Vero and Calu-3 cells

et al. 2022

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Stress granule formation is induced by numerous environmental stressors, including sodium arsenite treatment and viral infection. Accordingly, stress granules can inhibit viral propagation and function as part of the antiviral host response to numerous viral infections. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) antagonizes stress granule formation, in part, via interaction between SARS-CoV-2 nucleocapsid (N) protein and Ras-GTPase-activating SH3-domain-binding protein 1 (G3BP1). However, it is unclear whether there are differential effects in different cell types. In this study, we assessed interaction between the N protein of SARS-CoV-2 S clade and G3BP1/2 in Vero and Calu-3 cells and investigated the effect of various SARS-CoV-2 strains on sodium arsenite-induced stress granule formation. Our data show that SARS-CoV-2 S clade N protein interacts with both G3BP1 and G3BP2 more strongly in Calu-3 vs. Vero cells. Consistent with this observation, infection with SARS-CoV-2 S clade induces stress granule formation in Vero but not in Calu-3 cells. However, infection with SARS-CoV-2 S clade, as well as other SARS-CoV-2 variants, inhibits sodium arsenite-induced stress granule formation in both cell lines. Taken together, our results show differential effects of SARS-CoV-2 infection on stress granule formation that is dependent on host cell type, rather than virus strain type.

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“…Sertoli cells also express the antiviral peptide PKR in response to stimulation by IFN-γ ( 81 ). The role of PKR in combating viral infections is to inhibit translation of viral mRNA and stimulate apoptosis of the infected cell ( 82 ). Furthermore, PKR also participates in a positive feedback loop with IFNs, amplifying the antiviral response ( 82 ).…”

Section: Sertoli Cell Protection From Pathogensmentioning

confidence: 99%

Sertoli Cell Immune Regulation: A Double-Edged Sword

et al. 2022

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The testis must create and maintain an immune privileged environment to protect maturing germ cells from autoimmune destruction. The establishment of this protective environment is due, at least in part, to Sertoli cells. Sertoli cells line the seminiferous tubules and form the blood-testis barrier (BTB), a barrier between advanced germ cells and the immune system. The BTB compartmentalizes the germ cells and facilitates the appropriate microenvironment necessary for spermatogenesis. Further, Sertoli cells modulate innate and adaptive immune processes through production of immunoregulatory compounds. Sertoli cells, when transplanted ectopically (outside the testis), can also protect transplanted tissue from the recipient’s immune system and reduce immune complications in autoimmune diseases primarily by immune regulation. These properties make Sertoli cells an attractive candidate for inflammatory disease treatments and cell-based therapies. Conversely, the same properties that protect the germ cells also allow the testis to act as a reservoir site for infections. Interestingly, Sertoli cells also have the ability to mount an antimicrobial response, if necessary, as in the case of infections. This review aims to explore how Sertoli cells act as a double-edged sword to both protect germ cells from an autoimmune response and activate innate and adaptive immune responses to fight off infections.

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Inhibition of PKR by Viruses

Cited by 56 publications

References 133 publications

dsRNA-induced condensation of antiviral proteins modulates PKR activity

dsRNA-induced condensation of antiviral proteins modulates PKR activity

Differential effect of SARS-CoV-2 infection on stress granule formation in Vero and Calu-3 cells

Sertoli Cell Immune Regulation: A Double-Edged Sword

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