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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 Article has an altmetric score of 10

Activation of the unfolded protein response and autophagy after hepatitis C virus infection suppresses innate antiviral immunity in vitro

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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 12

Abrogation of the UPR-autophagy–mediated suppression of IFN-β activation by knockdown of LAMP2 and Rab7.

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Abrogation of the UPR-autophagy–mediated suppression of IFN-β activation...
(A) Huh7/mRFP-GFP-LC3 cells were transfected with 400 pmol each of control, LAMP2, or Rab7 siRNA duplexes for 48 hours, and cells were quantified for RFP-LC3– (RFP-positive) and RFP-GFP-LC3–labeled (RFP-GFP-positive) puncta structures by confocal microscopy (bottom panel). The yellow-colored image represents the RFP-GFP-LC3–labeled puncta structure. A set of representative confocal images is also shown (top panel; scale bars: 10 μm). (B) Huh7/mRFP-GFP-LC3 cells were transfected with 400 pmol each of the indicated siRNA duplexes. Forty-eight hours later, cells were transfected with the pIFN-β/Fluc promoter reporter and cultured for 24 hours. The cells were then transfected with control HCV 5′-UTR RNA or 3′-UTR PAMP RNA and maintained for an additional 12 hours. The cells were left untreated or treated with EBSS or tunicamycin for 6 hours. Cells were then analyzed for IFNB promoter reporter activation (left panel). A set of cells 48 hours after siRNA transfection was analyzed by the Western blotting (right panel). (C and D) Huh7/mRFP-GFP-LC3 cells were infected with HCV at an MOI of 10 and cultured for 6 days. The cells were then transfected with the indicated siRNA duplexes as described in A. Seventy-two hours after transfection, cells were harvested and analyzed for the intracellular HCV RNA level (C) and analyzed for the indicated proteins by Western blotting (D). Data represent mean ± SEM (n = 3) (A–C).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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