Immature Core protein of hepatitis C virus induces an unfolded protein response through inhibition of ERAD‐L in a yeast model system

Abstract

The structural protein Core of hepatitis C virus (HCV), a cytosolic protein, induces endoplasmic reticulum (ER) stress and unfolded protein response (UPR) in hepatocytes, and is responsible for the pathogenesis of persistent HCV infection. Using yeast as a model system, we evaluated mechanisms underlying Core-induced interference of ER homeostasis and UPR, and found that UPR is induced by the immature Core (aa 1-191, Core191) but not by the mature Core (aa 1-177, Core177). Interestingly, Core191 inhibits both ERAD-L, a degradation system responsible for misfolded/unfolded proteins in the ER lumen, and ERAD-M, a degradation system responsible for proteins carrying a misfolded/unfolded region in the ER membrane. In contrast, Core177 inhibits ERAD-M but not ERAD-L. In addition, requirement of an unfolded protein sensor in the ER lumen suggested that inhibition of ERAD-L is probably responsible for Core191-dependent UPR activation. These results implicate inadequate maturation of Core as a trigger for induction of ER stress and UPR.

Contribution of yeast models to virus research

“…On the other hand, HCV mature core 177 (aa 1-177) inhibited only ERAD-M and not ERAD-L. Hence, Takashi and colleagues suggested that HCV core 191 may play a role in the induction of UPR in yeast by inhibiting ERAD-L (Takahashi et al 2017).…”

Physiological functions of SPP/SPPL intramembrane proteases

“…The most intensively investigated example is the Hepatitis C virus (HCV) core protein which is required for subsequent assembly of viral particles at lipid droplets and therefore finally also virus production and propagation [ 98 – 101 ]. Loss of SPP leads to an impaired maturation of the HCV core protein and the subsequent TRC8-dependent degradation of the immature precursor through the ERAD pathway [ 102 , 103 ]. Due to its essential role in the viral life cycle, pharmacological inhibition of SPP can suppress HCV replication in cultured cells [ 104 ].…”

The molecular mechanism of induction of unfolded protein response by Chlamydia

“…These UPR transducers are kept inactive by binding to the ER chaperone GRP78/BiP (the master regulator of UPR) when the ER folding capacity is operating normally. Activators of UPR either cause the ER stress through depletion of Ca 2+ from the ER (14), or the accumulation of unfolded/misfolded, overexpressed or modified proteins in the ER, any of which dissociates the UPR transducers from BiP to activate UPR signaling (15, 16). …”

“…Mechanistically, Shiga toxigenic strains of Escherichia coli produce AB5 subtilase cytotoxin that binds to and inactivates BiP to activate the UPR transducers (20); Hepatitis C virus activates UPR at least in part due to the accumulation of immature core protein (Core 199) in the ER lumen (15), while L. monocytogenes require its cholesterol-dependent cytolysin toxin (listeriolysin O) to induce UPR (18). However, the mechanism of UPR activation by Chlamydia is not known.…”

“…Indeed, recent reports have demonstrated that Chlamydia , like certain other obligate intracellular microbial agents such as Brucella melitensis , Listeria monocytogenes and Hepatitis C virus, activate the UPR pathways to enhance their intracellular survival and replication (15, 17–19). Mechanistically, Shiga toxigenic strains of Escherichia coli produce AB5 subtilase cytotoxin that binds to and inactivates BiP to activate the UPR transducers (20); Hepatitis C virus activates UPR at least in part due to the accumulation of immature core protein (Core 199) in the ER lumen (15), while L. monocytogenes require its cholesterol-dependent cytolysin toxin (listeriolysin O) to induce UPR (18). However, the mechanism of UPR activation by Chlamydia is not known.…”