Mechanisms of protein kinase PKR-mediated amplification of beta interferon induction by C protein-deficient measles virus.
The measles virus P gene products V and C antagonize the host interferon (IFN) response, blocking both IFN signaling and production. Using Moraten vaccine strain-derived measles virus and isogenic mutants deficient for either V or C protein production (V(ko) and C(ko), respectively), we observed that the C(ko) virus was a potent inducer of IFN-beta, while induction by V(ko) virus was an order of magnitude lower than that by the C(ko) virus. The parental recombinant Moraten virus did not significantly induce IFN-beta. The enhanced IFN-inducing capacity of the C(ko) virus correlated with an enhanced activation of IFN regulatory factor 3 (IRF-3), NF-kappaB, and ATF-2 in C(ko)-infected compared to V(ko) or parental virus-infected cells. Furthermore, protein kinase PKR and mitochondrial adapter IPS-1 were required for maximal C(ko)-mediated IFN-beta induction, which correlated with the PKR-mediated enhancement of mitogen-activated protein kinase and NF-kappaB activation. Our results reveal multiple consequences of C protein expression and document an important function for PKR as an enhancer of IFN-beta induction during measles virus infection.
Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA 93106, USA.
Christopher S
CS
McAllister
Ann M
AM
Toth
Ping
P
Zhang
Patricia
P
Devaux
Roberto
R
Cattaneo
Charles E
CE
Samuel
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D000818:Animals; D002522:Chlorocebus aethiops; D005786:Gene Expression Regulation / Q000276:immunology*; D006367:HeLa Cells; D006801:Humans; D016899:Interferon-beta / Q000235:genetics*; D008459:Measles virus / Q000737:chemistry / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism; D014709:Vero Cells; D014764:Viral Proteins / Q000502:physiology*; D019892:eIF-2 Kinase / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; C505371:MAVS protein, human; D016328:NF-kappa B; D014764:Viral Proteins; D016899:Interferon-beta; D019892:eIF-2 Kinase