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The Leader Protein of Theiler's Virus Prevents the Activation of PKR
- Source :
- Journal of virology, Vol. 93, no. 19 (2019) (2019)
- Publication Year :
- 2019
- Publisher :
- American Society for Microbiology, 2019.
-
Abstract
- Leader (L) proteins encoded by cardioviruses are multifunctional proteins that contribute to innate immunity evasion. L proteins of Theiler’s murine encephalomyelitis virus (TMEV), Saffold virus (SAFV), and encephalomyocarditis virus (EMCV) were reported to inhibit stress granule assembly in infected cells. Here, we show that TMEV L can act at two levels in the stress granule formation pathway: on the one hand, it can inhibit sodium arsenite-induced stress granule assembly without preventing eIF2α phosphorylation and, thus, acts downstream of eIF2α; on the other hand, it can inhibit eucaryotic translation initiation factor 2 alpha kinase 2 (PKR) activation and the consequent PKR-mediated eIF2α phosphorylation. Interestingly, coimmunostaining experiments revealed that PKR colocalizes with viral double-stranded RNA (dsRNA) in cells infected with L-mutant viruses but not in cells infected with the wild-type virus. Furthermore, PKR coprecipitated with dsRNA from cells infected with L-mutant viruses significantly more than from cells infected with the wild-type virus. These data strongly suggest that L blocks PKR activation by preventing the interaction between PKR and viral dsRNA. In infected cells, L also rendered PKR refractory to subsequent activation by poly(I·C). However, no interaction was observed between L and either dsRNA or PKR. Taken together, our results suggest that, unlike other viral proteins, L indirectly acts on PKR to negatively regulate its responsiveness to dsRNA. IMPORTANCE The leader (L) protein encoded by cardioviruses is a very short multifunctional protein that contributes to evasion of the host innate immune response. This protein notably prevents the formation of stress granules in infected cells. Using Theiler’s virus as a model, we show that L proteins can act at two levels in the stress response pathway leading to stress granule formation, the most striking one being the inhibition of eucaryotic translation initiation factor 2 alpha kinase 2 (PKR) activation. Interestingly, the leader protein appears to inhibit PKR via a novel mechanism by rendering this kinase unable to detect double-stranded RNA, its typical activator. Unlike other viral proteins, such as influenza virus NS1, the leader protein appears to interact with neither PKR nor double-stranded RNA, suggesting that it acts indirectly to trigger the inhibition of the kinase.
- Subjects :
- Picornavirus
viruses
Immunology
Microbiology
double-stranded RNA virus
Virus
Cell Line
Viral Proteins
eIF-2 Kinase
leader protein
Stress granule
Theilovirus
Virology
Animals
Humans
Stress granule assembly
Immune Evasion
RNA, Double-Stranded
Innate immune system
biology
Theiler's murine encephalomyelitis virus
virus diseases
RNA
PKR
biochemical phenomena, metabolism, and nutrition
cardiovirus
biology.organism_classification
Protein kinase R
Virus-Cell Interactions
Cell biology
Enzyme Activation
picornavirus
Insect Science
Host-Pathogen Interactions
RNA, Viral
Double-stranded RNA viruses
Protein Binding
Subjects
Details
- ISSN :
- 10985514 and 0022538X
- Volume :
- 93
- Database :
- OpenAIRE
- Journal :
- Journal of Virology
- Accession number :
- edsair.doi.dedup.....ad5660dbdf64af8bc979573d012262e8