Biology Reference
In-Depth Information
(c-FLIP), a key regulator of the death-inducing signaling complex,
and to suppress its anti-apoptotic effects.
80
In chronic and fulminant
hepatitis B patients the Fas/FasL system has also been shown to be
important for liver injury.
81,82
By sensitizing liver cells to TNF and
FasL, HBV promotes liver injury, an event that precedes cirrhosis
and hepatocarcinogenesis. Further, since TNF sensitization can be
overcome by mitogenic factors, this may also be a mechanism to
select for neoplastic hepatocytes that survive by synthesizing large
amounts of growth factors.
Endoplasmic reticulum stress
The endoplasmic reticulum (ER) is sensitive to a variety of cellular
stresses, including viral infection, alterations in calcium levels, inhibi-
tion of protein glycosylation, etc.
83
Excessive protein synthesis and
accumulation of unfolded or misfolded proteins lead to ER stress trig-
gering the unfolded protein response (UPR) and protein degrada-
tion. This signaling pathway is mediated by three ER resident sensor
proteins: the type-I ER transmembrane protein kinase IRE-1, the
activating transcription factor 6 (ATF-6) and the PKR-like ER kinase
(PERK). In the absence of ER stress, the ER resident protein GRP78
is associated with each of the sensors.
84-86
Upon accumulation of
unfolded/misfolded proteins, GRP78 dissociates from its partners,
activating the different pathways (Fig. 5).
Subgenomic replicons of HCV as well as expression of the NS5A
protein alone induces ER stress, as observed by the appearance of a
transcriptionally active form of the ATF protein, ATF6
(N). This
translocates to the nucleus, where it transcriptionally activates ER
chaperones.
84-86
HCV compels cells to adapt to ER stress by different
mechanisms. Cells harboring HCV replicons have lower levels of
eIF2
α
phosphorylation, indicating that the overall protein synthesis is
higher.
87
HCV E2 modulates global translation by inhibition of IFN-
induced PKR as well as by binding and inhibiting PERK. HCV infection
can suppress the degradation of misfolded proteins and simultane-
ously stimulate the synthesis of the viral protein in the ER. The IRE1-
XBP1 (X-box binding protein) pathway directs both protein refolding
α
