Hepatitis C virus core protein modulates the interferon-induced transacting factors of Jak/Stat signaling pathway but does not affect the activation of downstream IRF-1 or 561 gene
A. Basu et al., Hepatitis C virus core protein modulates the interferon-induced transacting factors of Jak/Stat signaling pathway but does not affect the activation of downstream IRF-1 or 561 gene, VIROLOGY, 288(2), 2001, pp. 379-390
Hepatitis C virus (HCV) has a propensity to cause chronic infection, with a
low proportion of patients exhibiting a sustained response to interferon-a
lpha (IFN alpha) therapy. An earlier report suggested that HCV inhibits IFN
alpha -induced signal transduction through the Jak/Stat pathway by prevent
ing the formation of the transacting factor ISGF3 complex, although the eff
ect on downstream pathway and the specific viral protein responsible for in
hibition of IFN alpha -mediated signal transduction were not elucidated. HC
V core protein displays a number of intriguing functional properties and ha
s been implicated in virus-mediated pathogenesis. In this study, we have an
alyzed the effect of core protein upon IFN alpha- or IFN gamma -induced reg
ulation of the Jak/Stat signaling pathway. HCV core protein expression exhi
bited a reduced Stat1 expression in I FN-treated mammalian cells. A gel ret
ardation assay suggested a reduced level of formation of the transacting fa
ctors, GAF and ISGF3, in IFN-treated cells. Further studies from protein ex
pression and RNase protection assay revealed that the reduced level of GAF
or ISGF3 formation could be attributed to modulation of Stat1 protein expre
ssion, an important player for innate immunity in host defense mechanism. H
owever, these modulatory effects did not interfere with the activation of t
he downstream effector genes, IRF-1 and 561, in IFN-treated cells. Stable t
ransfectants of cells after introduction of a plasmid DNA encoding both the
structural and the nonstructural proteins of HCV also exhibited a similar
effect. Taken together, these results suggest that although expression of t
he core protein alone or with other HCV proteins modulate transacting facto
rs of Jak/Stat signaling pathway, expression of the downstream effector gen
es IRF-1 and 561 remains unaffected upon IFN treatment and may contribute t
o host defense mechanism. (C) 2001 Academic Press.