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three forms and restores virus particle formation. 90 The hepatitis
E virus capsid (ORF2) protein has recently been shown to use the ER
associated degradation (ERAD) pathway to retrotranslocate from the
ER back into the cytoplasm to interfere with I
κ
B ubiquitination as a
means to regulate NF
B activity. 91 The functional consequences of
this on HEV pathogenesis remain to be understood.
κ
Reactive oxygen species (ROS)
Cellular oxidative stress is characterized by an increase in the intracel-
lular levels of reactive oxygen species (ROS) that can affect cell sur-
vival as well as death pathways. ROS can function as a key player in
different signaling cascades by activating transcription factors such as
NF
B and STAT3 92,93 that are involved in a wide variety of cellular
functions ranging from cellular growth, proliferation, DNA replica-
tion and repair to functions involved in cell death and cancer devel-
opment. 94 ER stress can release calcium from intracellular ER stores
into the cytosol, and this can trigger oxidative stress, activate NF
κ
B
and modulate the mitochondrial death pathway (Fig. 5). Increased
intracellular calcium can activate calpains that cleave and inactivate the
anti-apoptotic Bcl-X L protein, and can also activate caspase 12. Increased
production of ROS has been observed in the livers of chronically
infected HBV and HCV patients. The HBx protein induces oxidative
stress and elevates ROS production by its direct association with the
voltage-dependent anion channel 3 (VDAC3) protein in the mito-
chondrial outer membrane. This interaction leads to a decrease in the
mitochondrial membrane potential and elevates ROS. 95 A mutant
HBx not able to translocate to mitochondria but capable of binding
to VDAC3 failed to elevate ROS levels. 94 In turn, HBx levels were
also found to be regulated by cellular ROS levels. 96 Therefore, intra-
cellular microenvironments generating ROS, such as severe inflam-
mation, may aggravate the pathogenesis of liver disease by accumulating
the HBx protein. The HCV NS5A protein also induces ER stress,
causes alteration of calcium homeostasis, and triggers ROS elevation. 97
These events result in activation and translocation of transcription
factors including STAT3 and NF
κ
κ
B to the nucleus. The HEV ORF3
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