Hepatitis Viruses, Signaling Events and Modulation of the Innate Host Response - Structure-Based Study of Viral Replication - page 102

Within this complex, the STAT proteins (STAT1 and STAT2)
undergo tyrosine phosphorylation, and this acts as a signal for their
dimerization through complementary pTyr/SH2 interactions. These
STAT1 and STAT2 homo- and heterodimers translocate to the
nucleus and, together with a protein called p48 (IRF-9), form a mul-
timeric transcription factor called ISGF3. In turn, ISGF3 binds to the
IFN stimulated response element (ISRE) within the promoters of
IFN-stimulated genes (ISGs) and activates their transcription. Stimu-
lation with IL-6 also leads to the phosphorylation of JAK1, JAK2 and
STAT3, followed by nuclear translocation of the STAT3 homodimer.
As expected, cytokine signaling through the Jak/STAT pathway is
tightly controlled by various mechanisms that involve inactivation or
removal of activated STAT molecules. 57 Induction of SOCS (suppres-
sors of cytokine signaling) also negatively regulates this pathway. 58-60
The SOCS proteins bind to Jak family tyrosine kinases, resulting in
the inhibition of tyrosine phosphorylation of Janus kinases and STAT
factors. 57
A number of viruses are known to modulate the JAK-STAT sig-
naling pathway by using various mechanisms (Goodbourn 2000).
Expression of the full-length HCV ORF suppresses the IFN-mediated
STAT/DNA binding activity. 61 The HCV core protein binds JAK and
has inhibitory effects on the JAK/STAT pathway. Constitutive expres-
sion of the HCV core protein reduces tyrosine phosphorylation of the
JAK and STAT proteins, thereby modifying STAT-mediated transcrip-
tion of ISGs. Point or deletion mutants of the HCV core protein,
which do not bind the JAK proteins, show no inhibitory effects on the
JAK-STAT pathway following IL-6 stimulation of murine CL2 and
human HepG2 cells. 62 The HCV core protein further induces the
expression of SOCS3, resulting in the inhibition of STAT1-tyrosine
phosphorylation. 63 Thus, HCV appears to have developed multiple
ways to interfere with the IFN-mediated host defense systems. 62,64
While the p48 subunit of ISGF3 is reported to be responsible for
the IFN -mediated suppression of HBV expression, 65 the X protein

of HBV (HBx) interacts with Jak1 and activates the JAK-STAT sig-
naling pathway. 66 There is sufficient evidence to indicate that the Jak/
STAT pathway is involved in cell proliferation and oncogenesis 67 ; this

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