The dsRNA protein kinase PKR: Virus and cell control

García, María Ángel; Meurs, Éliane; Esteban, Mariano

doi:10.1016/j.biochi.2007.03.001

Cited by 565 publications

(582 citation statements)

References 201 publications

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“…PKR is activated by binding to double-stranded RNA formed during viral replication; it phosphorylates the a-subunit of translation factor eIF2, resulting in inhibition of protein synthesis (Barber, 2005;Garcia et al, 2007). PKR has also been implicated in many additional cellular stress responses and corresponding signal transduction pathways, including the nuclear factor-kB and p38-mitogen-activated protein kinase pathways (reviewed by Barber, 2005;Garcia et al, 2006Garcia et al, , 2007. A major role for PKR has recently emerged in the control of apoptosis, following activation of the tumour-suppressor p53 pathway (Yoon et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Roles of the translationally controlled tumour protein (TCTP) and the double-stranded RNA-dependent protein kinase, PKR, in cellular stress responses

et al. 2009

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Section: Introductionmentioning

confidence: 99%

Roles of the translationally controlled tumour protein (TCTP) and the double-stranded RNA-dependent protein kinase, PKR, in cellular stress responses

et al. 2009

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“…They are detected through Toll-like receptors (TLRs) and TLR-independent molecules, including the RIG-I-like receptor (RLR) family (1,4). Several PRRs that trigger innate immune responses have been identified in the Reoviridae family; these include TLR3 (2), RIG-I and MDA5 (5,57,66), PKR (15,57), and the newly described TRIF-dependent DexD/H-box helicases (67). While viral PAMPs can trigger an antiviral response in most cells of the infected host, sensing mechanisms can vary greatly from one cell type to another.…”

mentioning

confidence: 99%

Sensing and Control of Bluetongue Virus Infection in Epithelial Cells via RIG-I and MDA5 Helicases

Chauveau

Doceul

Lara

et al. 2012

J Virol

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Bluetongue virus (BTV), an arthropod-borne member of the Reoviridae family, is a double-stranded RNA virus that causes an economically important livestock disease that has spread across Europe in recent decades. Production of type I interferon (alpha/beta interferon [IFN-␣/␤]) has been reported in vivo and in vitro upon BTV infection. However, the cellular sensors and signaling pathways involved in this process remain unknown. Here we studied the mechanisms responsible for the production of IFN-␤ in response to BTV serotype 8. Upon BTV infection of A549 cells, expression of IFN-␤ and other proinflammatory cytokines was strongly induced at both the protein and mRNA levels. This response appeared to be dependent on virus replication, since exposure to UV-inactivated virus failed to induce IFN-␤. We also demonstrated that BTV infection activated the transcription factors IFN regulatory factor 3 and nuclear factor B. We investigated the role of several pattern recognition receptors in this response and showed that expression of IFN-␤ was greatly reduced after small-interfering-RNA-mediated knockdown of the RNA helicase encoded by retinoic acid-inducible gene I (RIG-I) or melanoma differentiation-associated gene 5 (MDA5). In contrast, silencing of MyD88, Toll-like receptor 3, or the recently described DexD/H-box helicase DDX1 sensor had no or a weak effect on IFN-␤ induction, suggesting that the RIG-I-like receptor pathway is specifically engaged for BTV sensing. Moreover, we also showed that overexpression of either RIG-I or MDA5 impaired BTV expression in infected A549 cells. Overall, this indicates that RIG-I and MDA5 can both contribute to the recognition and control of BTV infection.

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“…RNA viruses potentially trigger apoptosis by activating cellular sensors designed to detect extraneous RNA derived from viral genomes or replicative intermediates. A well-described mechanism of cellular recognition of dsRNA is that mediated by PKR, which results in the inhibition of translation followed by apoptosis due to lack of protein expression (Garcia et al, 2007). Studies have also suggested a direct role for PKR in inducing apoptosis through caspase-8 and -9 (Iordanov et al, 2005a, b Previously, it was found that CSFV infection of primary porcine endothelial cells could counteract the pro-apoptotic effects of the dsRNA mimic pIpC (Bensaude et al, 2004).…”

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confidence: 99%

Classical swine fever virus infection protects aortic endothelial cells from pIpC-mediated apoptosis

Johns

Bensaude

Rocca

et al. 2009

Journal of General Virology

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Classical swine fever virus (CSFV) causes severe disease in pigs associated with leukopenia, haemorrhage and fever. We show that CSFV infection protects endothelial cells from apoptosis induced by the dsRNA mimic, pIpC, but not from other apoptotic stimuli, FasL or staurosporine. CSFV infection inhibits pIpC-induced caspase activation, mitochondrial membrane potential loss and cytochrome c release as well as the pro-apoptotic effects of truncated Bid (tBid) overexpression. The CSFV proteins N pro and E rns both contribute to CSFV inhibition of apoptosis. We conclude that CSFV infection can inhibit apoptotic signalling at multiple levels, including at the caspase-8 and the mitochondrial checkpoints. By supporting viral replication, endothelial cells may promote CSFV pathogenesis. INTRODUCTIONClassical swine fever virus (CSFV), a pestivirus within the family Flaviviridae, is related in terms of its sequence and genome organization to other members of the flavivirus group that give rise to human diseases such as hepatitis C and dengue fever. CSFV is a positive-sense RNA virus, and is the causative agent of classical swine fever (CSF), a notifiable disease of pigs (Le Potier et al., 2006). Disease outbreaks are associated with considerable economic loss and adverse effects on animal welfare (Paton & GreiserWilke, 2003). In its most virulent form, CSFV infection causes severe immunopathological signs, including leukopenia, haemorrhage and fever, accompanied by high morbidity and mortality. However, within an infected population, some animals are found to recover or develop chronic disease (Le Potier et al., 2006). These observations suggest a complex interplay between the virus and the host immune system. CSFV infection is accompanied by depression of cellular immune defences (Ganges et al., 2008) and particularly innate responses mediated by interferon (Bensaude et al., 2004; La Rocca et al., 2005; Ruggli et al., 2005;Seago et al., 2007). In vivo, elevated levels of cell death by apoptosis are thought to account for the characteristic depletion of circulating leukocytes (Sanchez-Cordon et al., 2002;Summerfield et al., 2000Summerfield et al., , 2001. However, it has been found that apoptotic cells rarely contain detectable viral antigen, indicating that apoptotic cells are generally not CSFV-infected (Choi et al., 2004;Sato et al., 2000;Summerfield et al., 2001). This finding, together with the observation that acutely infected animals develop high viral loads, suggest a possible role for cell populations that are resistant to virus-induced apoptosis. These may include endothelial cells.Apoptosis is a controlled cell death programme employed by multicellular organisms to eliminate damaged, aberrant or infected cells (Benedict et al., 2002). A characteristic of apoptotic cell death is the activation of the caspase family of proteases. Caspases that function near the apex of cell death cascades are designated initiators and include caspases-8 and -9, whereas those involved in the terminal stages of cell death, such as ...

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The dsRNA protein kinase PKR: Virus and cell control

Cited by 565 publications

References 201 publications

Roles of the translationally controlled tumour protein (TCTP) and the double-stranded RNA-dependent protein kinase, PKR, in cellular stress responses

Roles of the translationally controlled tumour protein (TCTP) and the double-stranded RNA-dependent protein kinase, PKR, in cellular stress responses

Sensing and Control of Bluetongue Virus Infection in Epithelial Cells via RIG-I and MDA5 Helicases

Classical swine fever virus infection protects aortic endothelial cells from pIpC-mediated apoptosis

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