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Enhanced Replication of Mouse Adenovirus Type 1 following Virus-Induced Degradation of Protein Kinase R (PKR)
- Source :
- mBio, mBio, Vol 10, Iss 2, p e00668-19 (2019), mBio, Vol 10, Iss 2 (2019)
- Publication Year :
- 2019
-
Abstract
- The first line of defense in cells during viral infection is the innate immune system, which is activated by different viral products. PKR is a part of this innate immune system and is induced by interferon and activated by dsRNA produced by DNA and RNA viruses. PKR is such an important part of the antiviral response that many viral families have gene products to counteract its activation or the resulting effects of its activity. Although a few RNA viruses degrade PKR, this method of counteracting PKR has not been reported for any DNA viruses. MAV-1 does not encode virus-associated RNAs, a human adenoviral defense against PKR activation. Instead, MAV-1 degrades PKR, and it is the first DNA virus reported to do so. The innate immune evasion by PKR degradation is a previously unidentified way for a DNA virus to circumvent the host antiviral response.<br />Protein kinase R (PKR) plays a major role in activating host immunity during infection by sensing double-stranded RNA (dsRNA) produced by viruses. Once activated by dsRNA, PKR phosphorylates the translation factor eukaryotic initiation factor 2α (eIF2α), halting cellular translation. Many viruses have methods of inhibiting PKR activation or its downstream effects, circumventing protein synthesis shutdown. These include sequestering dsRNA or producing proteins that bind to and inhibit PKR activation. Here we describe our finding that in multiple cell types, PKR was depleted during mouse adenovirus type 1 (MAV-1) infection. MAV-1 did not appear to be targeting PKR at the transcriptional or translational level, because total PKR mRNA levels and levels of PKR mRNA bound to polysomes were unchanged or increased during MAV-1 infection. However, inhibiting the proteasome reduced the PKR depletion seen in MAV-1-infected cells, whereas inhibiting the lysosome had no effect. This suggests that proteasomal degradation alone is responsible for PKR degradation during MAV-1 infection. Time course experiments indicated that the degradation occurs early after infection. Infecting cells with UV-inactivated virus prevented PKR degradation, whereas inhibiting viral DNA replication did not. Together, these results suggest that an early viral gene is responsible. Degradation of PKR is a rare mechanism to oppose PKR activity, and it has been described in only six RNA viruses. To our knowledge, this is the first example of a DNA virus counteracting PKR by degrading it.
- Subjects :
- Proteasome Endopeptidase Complex
viruses
Protein degradation
eIF2alpha kinase
Virus Replication
Microbiology
environment and public health
Virus
Cell Line
Host-Microbe Biology
03 medical and health sciences
Mastadenovirus
Mice
eIF-2 Kinase
0302 clinical medicine
Interferon
Virology
Eukaryotic initiation factor
medicine
Animals
Translation factor
030304 developmental biology
Immune Evasion
0303 health sciences
Innate immune system
Chemistry
030302 biochemistry & molecular biology
RNA
virus diseases
DNA virus
PKR
biochemical phenomena, metabolism, and nutrition
Protein kinase R
QR1-502
Immunity, Innate
3. Good health
Cell biology
RNA silencing
enzymes and coenzymes (carbohydrates)
proteasome
protein stability
adenoviruses
030220 oncology & carcinogenesis
Host-Pathogen Interactions
Proteolysis
protein degradation
medicine.drug
Research Article
Subjects
Details
- ISSN :
- 21507511
- Volume :
- 10
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- mBio
- Accession number :
- edsair.doi.dedup.....47ba4a71c35db3733e757f05206a09b1