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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Research Article Virology

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 11

Interference with the UPR-autophagy inducer–triggered repression of IFN-β activation by CQ.

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Interference with the UPR-autophagy inducer–triggered repression of IFN-...
(A and B) Huh7/mRFP-GFP-LC3 cells were transfected with the pIFN-β/Fluc promoter reporter and cultured for 24 hours. Cells were then transfected with control HCV 5′-UTR RNA or 3′-UTR PAMP RNA and then maintained for an additional 12 hours. Transfected cells were left untreated or treated with rapamycin (A) or DTT (B) in the presence or absence of CQ as described in the legend to Figure 10, A and B. The fold increase in the IFNB promoter activity of viral PAMP RNA–transfected cells was determined by normalization to the basal level of the control RNA–transfected cells. (C and D) The effect of CQ on rapamycin-induced (C) or DTT-induced (C) suppression of DEV PAMP–mediated IFNB promoter activation was assessed as described in A and B. Data represent mean ± SEM (n = 3).