Biology Reference
In-Depth Information
pathway. The dsRNA-dependent serine/threonine protein kinase
PKR is a key IFN-inducible protein. Two motifs in amino terminus of
PKR bind dsRNA leading to its activation, dimerization and
autophosphorylation. Activated PKR catalyzes the phosphorylation of
several substrate proteins, the best characterized being the
1 subunit
of the eukaryotic protein synthesis initiation factor 2 (eIF2
α
α
).
Phosphorylation of eIF2
increases its affinity for GDP, thus inhibit-
ing the GDP-GTP exchange that is necessary for continuing transla-
tion. This shuts down host as well as viral protein synthesis,
19
leading
to death of the infected cell.
Hepatitis viruses have developed several strategies to counter the
effects of PKR. The HCV NS5A protein prevents PKR dimerization
and activation,
20
thereby preventing PKR-mediated translation inhibi-
tion
20-22
(Fig. 2). Exogenously expressed NS5A was found to confer
interferon resistance to vesicular stomatitis virus (VSV), which is oth-
erwise sensitive to interferon.
23,24
Mutations within the NS5A region
termed as the IFN sensitivity-determining region (ISDR) disrupt the
ability of NS5A to bind PKR and inhibit the catalytic activity of PKR.
The HCV envelope E2 protein contains a sequence identical to the
phosphorylation sites of PKR and eIF2
α
. As a result, the E2 protein
can bind and disrupt PKR dimerization, and inhibit its catalytic
activity.
25
These combined effects of NS5A and E2 on PKR activation
are proposed to be responsible for HCV persistence.
26-29
A reduction
in PKR levels has also been observed in HCC tumor tissues of HBV
patients, suggesting a possible role of PKR in promoting tumor
growth.
30
The activation of PKR also affects the status of Nuclear Factor
kappa B (NF
α
B), a member of the Rel family of proteins and a tran-
scription factor central to the expression of various immune regula-
tory genes.
31
In a quiescent cell, NF
κ
B is present in the cytoplasm in
an inactive state as a p65/p50 heterodimer bound to the inhibitor of
NF
κ
κ
B (I
κ
B) protein. On phosphorylation of I
κ
B, the complex disso-
B into the nucleus, where it reg-
ulates the expression of multiple genes. Activated PKR leads to the
phosphorylation of I
ciates, allowing the transport of NF
κ
κ
B,
32
possibly through phosphorylation of its
upstream I
κ
B kinase (IKK).
33
In the nucleus, NF
κ
B binds to the IFN
γ
