Activation of the unfolded protein response and autophagy after hepatitis C virus infection suppresses innate antiviral immunity in vitro
Po-Yuan Ke, Steve S.-L. Chen
Po-Yuan Ke, Steve S.-L. Chen
Published December 6, 2010
Citation Information: J Clin Invest. 2011;121(1):37-56. https://doi.org/10.1172/JCI41474.
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Activation of the unfolded protein response and autophagy after hepatitis C virus infection suppresses innate antiviral immunity in vitro

Abstract

Autophagy, a process for catabolizing cytoplasmic components, has been implicated in the modulation of interactions between RNA viruses and their host. However, the mechanism underlying the functional role of autophagy in the viral life cycle still remains unclear. Hepatitis C virus (HCV) is a single-stranded, positive-sense, membrane-enveloped RNA virus that can cause chronic liver disease. Here we report that HCV induces the unfolded protein response (UPR), which in turn activates the autophagic pathway to promote HCV RNA replication in human hepatoma cells. Further analysis revealed that the entire autophagic process through to complete autolysosome maturation was required to promote HCV RNA replication and that it did so by suppressing innate antiviral immunity. Gene silencing or activation of the UPR-autophagy pathway activated or repressed, respectively, IFN-β activation mediated by an HCV-derived pathogen-associated molecular pattern (PAMP). Similar results were achieved with a PAMP derived from Dengue virus (DEV), indicating that HCV and DEV may both exploit the UPR-autophagy pathway to escape the innate immune response. Taken together, these results not only define the physiological significance of HCV-induced autophagy, but also shed light on the knowledge of host cellular responses upon HCV infection as well as on exploration of therapeutic targets for controlling HCV infection.

Authors

Po-Yuan Ke, Steve S.-L. Chen

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Figure 8

The effect of UPR-autophagy gene silencing on chemical inducer–mediated suppression of IFN-β activation.

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The effect of UPR-autophagy gene silencing on chemical inducer–mediated ...
(A and B) VEC (A) and ATG5KD (B) Huh7 cells were transfected with the IFNB promoter reporter and cultured for 24 hours. The cells were then transfected with HCV control HCV 5′-UTR RNA or 3′-UTR PAMP RNA and maintained for an additional 12 hours. Transfected cells were left untreated, or treated with EBSS or HBSS for 6 hours, and then IFNB promoter reporter activation determined (upper right panels). Another set of cells without DNA and RNA transfections was handled in parallel prior to quantification for endogenous LC3B-labeled puncta structures by immunostaining (upper left and bottom panels, scale bars: 10 μm). (C and D) VEC (C) and CHOPKD (D) Huh7 cells were transfected with the IFNB promoter reporter and HCV 3′-UTR PAMP RNA and then treated with 2 mM DTT or 4 μg/ml tunicamycin for 6 hours before assessment of IFNB promoter reporter activation (upper right panels). Another set of cells without DNA and RNA transfections was handled in parallel and then quantified for LC3B-labeled puncta structures (upper left and bottom panels; scale bars: 10 μm). Data represent mean ± SEM (n = 3).