Double-stranded RNA-activated protein kinase interacts with apoptosis signal-regulating kinase 1 - Implications for apoptosis signaling pathways

Double-stranded RNA-activated protein kinase (PKR), a serine/threonine kinase, is activated in virus-infected cells and acts as an antiviral machinery of type I interferons. PKR controls several stress response pathways induced by double-stranded RNA, tumor necrosis factor-alpha or lipopolysaccharide, which result in the activation of stress-activated protein kinase/c-Jun NH2 -terminal kinase and p38 of the mitogen-activated protein kinase family. Here we showed a novel interaction between PKR and apoptosis signal-regulating kinase 1 (ASK1), one of the members of the mitogen-activated protein kinase kinase kinase family, which is activated in response to a variety of apoptosis-inducing stimuli. PKR and ASK1 showed predominant cytoplasmic localization in COS-1 cells transfected with both cDNAs, and coimmunoprecipitated from the cell extracts. A dominant negative mutant of PKR (PKR-KR) inhibited both the apoptosis and p38 activation induced by ASK1 in vivo . Consistently, PKR-KR inhibited the autophosphorylation of ASK1 in vitro , and exposure to poly(I)-poly(C) increased the phosphorylation of ASK1 in vivo . These results indicate the existence of a link between PKR and ASK1, which modifies downstream MAPK.