Figure 1.

Hepatic adaptive response to multifaceted stress generated during chronic hepatitis C virus (HCV) infection is called the integrated stress response (ISR). Shown is the summary of multifaceted stress response generated during chronic HCV infection that is associated with the risk of liver disease progression. In addition to the direct virus-induced ER stress/UPR gene expression, many different cellular stress signals are induced in HCV-infected cells due to a shift in host cell metabolism. There are four different stress kinases participate in the generation of multifaceted stress response. Stress signals during HCV infection activate PKR, GCN2, PERK, and HRI kinases that stimulate phosphorylation of eIF2α, the core element of the stress response, which inhibits cellular translation. Under normal conditions with low levels of phosphorylated eIF2α promotes cap-dependent translation. During the ISR, cellular translation is attenuated due to increased eIF2α phosphorylation, which supports the translation of specific gene (ATF4) needed for cell survival. The PERK-eIF2α-ATF4 activation has been associated with autophagy induction and cell survival. If the stress becomes severe this can also activate NRF2 transcription and chaperone-mediated autophagy (CMA) activation.