Biology Reference
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promoter and is part of the enhanceasome that contains multiple tran-
scription factors and the IFN regulatory factor (IRF) proteins (Fig. 2).
The IRF proteins are a family of transcription factors (IRF 1-9)
that regulate the expression of several genes transcriptionally respon-
sive to IFN.
34-36
Within this family, IRF3 and IRF7 have been identi-
fied as key regulators of IFN
induction.
37
IRF3 is constitutively
expressed in many cell types and is localized to the cytoplasm of nor-
mal uninfected cells. Upon virus infection or in the presence of
dsRNA, IRF3 is activated by phosphorylation in its C-terminus by a
virus-activated kinase (VAK). Some of the components of VAK include
IKK-related kinase, IKK
α
/
β
and a TANK binding kinase (TBK1)
38
(Fig. 2).
Phosphorylation of IRF3 causes its dimerization and translocation to
the nucleus, where it binds regulatory elements leading to the tran-
scription of the genes for IFN
ε
, the chemokine RANTES and
other proteins that inhibit viral infection. Viral infection also stimu-
lates IRF7 synthesis. Phosphorylation of IRF7 by VAK causes its
translocation to the nucleus, where it forms a heterodimer with IRF3
and activates the expression of IFN
α
and
β
B and
IRFs act as potent stimulators of interferons and several other cytokines
that can mount an inflammatory response and contribute to the clear-
ance of viral infection. Understandably then, several viruses have tar-
geted these pathways to establish infection in the host.
The HCV encoded NS3/4A serine protease inhibits the phos-
phorylation of IRF3,
39
thereby preventing its nuclear translocation
and downstream functions (Fig. 2). Expression of the HCV polypep-
tide or the presence of replicating HCV genome prevents induction
of the IRF3 pathway by Sendai virus that is otherwise a potent acti-
vator of IRF3.
39
The serine protease activity of NS3/4A is required for
this inhibition, suggesting that the protease may target upstream activa-
tors like VAK for proteolytic degradation. Further, reporter assays have
shown the baseline activity of the interferon stimulated response element
(ISRE) to be significantly lower in cells harboring the HCV replicon
compared to control cells.
40
The expression of IRF1 was also found to
be significantly lower in cells expressing the replicon.
40
The NS5A pro-
tein blocks the phosphorylation/activation of IRF1 and the induction
of IRF1-dependent promoter activation.
41-43
Noncytopathogenic strains
α
genes. Thus, together NF
κ
