PERSISTENT ACTIVATION OF RELA BY RESPIRATORY SYNCYTIAL VIRUS INVOLVESPROTEIN-KINASE-C, UNDERPHOSPHORYLATED I-KAPPA-B-BETA, AND SEQUESTRATION OF PROTEIN PHOSPHATASE 2A BY THE VIRAL PHOSPHOPROTEIN
V. Bitko et S. Barik, PERSISTENT ACTIVATION OF RELA BY RESPIRATORY SYNCYTIAL VIRUS INVOLVESPROTEIN-KINASE-C, UNDERPHOSPHORYLATED I-KAPPA-B-BETA, AND SEQUESTRATION OF PROTEIN PHOSPHATASE 2A BY THE VIRAL PHOSPHOPROTEIN, Journal of virology, 72(7), 1998, pp. 5610-5618
Respiratory syncytial virus (RSV) activated the RelA (p65) subunit of
nuclear factor kappa B (NF-kappa B) over many hours postinfection. The
initial activation coincided with phosphorylation and degradation of
I kappa B alpha, the cytoplasmic inhibitor of RelA, During persistent
activation of NF-kappa B at later times in infection, syntheses of inh
ibitors I kappa B beta as well as I kappa B beta were restored. Howeve
r, the resynthesized I kappa B beta was in an underphosphorylated stat
e, which apparently prevented inhibition of NF-kappa B. Use of specifi
c inhibitors suggested that the pathway leading to the persistent-but
not the initial-activation of NF-kappa B involved signaling through pr
otein kinase C (PKC) and reactive oxygen intermediates of nonmitochond
rial origin, whereas phospholipase C or D played little or no role. Th
us, RSV infection led to the activation of NF-kappa B by a biphasic me
chanism: a transient or early activation involving phosphorylation of
the inhibitor I kappa B polypeptides, and a persistent or long-term ac
tivation requiring PKC and the generation of hypophosphorylated I kapp
a B beta. At least a part of the activation was through a novel mechan
ism in which the viral phosphoprotein P associated with but was not de
phosphorylated by protein phosphatase 2A and thus sequestered and inhi
bited the latter. We postulate that this led to a net increase in the
phosphorylation state of signaling proteins that are responsible for R
elA activation.