Key result
Depletion of PKR in HeLa cells impaired the phosphorylation of p38 and JNK induced by DeltaE3L mutant vaccinia virus or dsRNA, which was dependent on the mitochondrial adapter IPS-1.
The study demonstrates that PKR is essential for the activation of p38 and JNK MAPKs following viral infection, acting through the RIG-I-like receptor pathway and mitochondrial adapter IPS-1.
PKR-IPS-1 signaling may shape antiviral MAPK responses; leaves open in vivo relevance and therapeutic targeting in humans.
The p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs) play important roles in the host innate immune response. The protein kinase regulated by RNA (PKR) is implicated in p38 MAPK activation in response to proinflammatory signals in mouse embryonic fibroblasts. To test the role of PKR in the activation of p38 and JNK MAPKs in human cells following viral infection, HeLa cells made stably deficient in PKR by using an RNA interference strategy were compared to cells with sufficient PKR. The phosphorylation of both p38 and JNK in cells with sufficient PKR was activated following either infection with an E3L deletion (DeltaE3L) mutant of vaccinia virus or transfection with double-stranded RNA (dsRNA) in the absence of infection with wild-type vaccinia virus. The depletion of PKR by stable knockdown impaired the phosphorylation of both p38 and JNK induced by either the DeltaE3L mutant virus or dsRNA but not that induced by tumor necrosis factor alpha. The PKR-dependent activation of MAPKs in DeltaE3L mutant-infected cells was abolished by treatment with cytosine beta-d-arabinoside. The complementation of PKR-deficient cells with the human PKR wild-type protein, but not with the PKR catalytic mutant (K296R) protein, restored p38 and JNK phosphorylation following DeltaE3L mutant virus infection. Transient small interfering RNA knockdown established that the p38 and JNK kinase activation following DeltaE3L infection was dependent upon RIG-I-like receptor signal transduction pathway components, including the mitochondrial adapter IPS-1 protein.
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Zhang et al. (2009) studied Viral infection (in vitro). PKR depletion (via RNA interference) vs. Cells with sufficient PKR was evaluated on Phosphorylation of p38 and JNK MAPKs. Depletion of PKR in HeLa cells impaired the phosphorylation of p38 and JNK induced by DeltaE3L mutant vaccinia virus or dsRNA, which was dependent on the mitochondrial adapter IPS-1.
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