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Hepatitis C Virus Core Protein Abrogates the DDX3 Function That Enhances IPS-1-Mediated IFN–Beta Induction

The DEAD box helicase DDX3 assembles IPS-1 (also called Cardif, MAVS, or VISA) in non-infected human cells where minimal amounts of the RIG-I-like receptor (RLR) protein are expressed. DDX3 C-terminal regions directly bind the IPS-1 CARD-like domain as well as the N-terminal hepatitis C virus (HCV)...

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Autores principales: Oshiumi, Hiroyuki, Ikeda, Masanori, Matsumoto, Misako, Watanabe, Ayako, Takeuchi, Osamu, Akira, Shizuo, Kato, Nobuyuki, Shimotohno, Kunitada, Seya, Tsukasa
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2999533/
https://www.ncbi.nlm.nih.gov/pubmed/21170385
http://dx.doi.org/10.1371/journal.pone.0014258
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author Oshiumi, Hiroyuki
Ikeda, Masanori
Matsumoto, Misako
Watanabe, Ayako
Takeuchi, Osamu
Akira, Shizuo
Kato, Nobuyuki
Shimotohno, Kunitada
Seya, Tsukasa
author_facet Oshiumi, Hiroyuki
Ikeda, Masanori
Matsumoto, Misako
Watanabe, Ayako
Takeuchi, Osamu
Akira, Shizuo
Kato, Nobuyuki
Shimotohno, Kunitada
Seya, Tsukasa
author_sort Oshiumi, Hiroyuki
collection PubMed
description The DEAD box helicase DDX3 assembles IPS-1 (also called Cardif, MAVS, or VISA) in non-infected human cells where minimal amounts of the RIG-I-like receptor (RLR) protein are expressed. DDX3 C-terminal regions directly bind the IPS-1 CARD-like domain as well as the N-terminal hepatitis C virus (HCV) core protein. DDX3 physically binds viral RNA to form IPS-1-containing spots, that are visible by confocal microscopy. HCV polyU/UC induced IPS-1-mediated interferon (IFN)-beta promoter activation, which was augmented by co-transfected DDX3. DDX3 spots localized near the lipid droplets (LDs) where HCV particles were generated. Here, we report that HCV core protein interferes with DDX3-enhanced IPS-1 signaling in HEK293 cells and in hepatocyte Oc cells. Unlike the DEAD box helicases RIG-I and MDA5, DDX3 was constitutively expressed and colocalized with IPS-1 around mitochondria. In hepatocytes (O cells) with the HCV replicon, however, DDX3/IPS-1-enhanced IFN-beta-induction was largely abrogated even when DDX3 was co-expressed. DDX3 spots barely merged with IPS-1, and partly assembled in the HCV core protein located near the LD in O cells, though in some O cells IPS-1 was diminished or disseminated apart from mitochondria. Expression of DDX3 in replicon-negative or core-less replicon-positive cells failed to cause complex formation or LD association. HCV core protein and DDX3 partially colocalized only in replicon-expressing cells. Since the HCV core protein has been reported to promote HCV replication through binding to DDX3, the core protein appears to switch DDX3 from an IFN-inducing mode to an HCV-replication mode. The results enable us to conclude that HCV infection is promoted by modulating the dual function of DDX3.
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spelling pubmed-29995332010-12-17 Hepatitis C Virus Core Protein Abrogates the DDX3 Function That Enhances IPS-1-Mediated IFN–Beta Induction Oshiumi, Hiroyuki Ikeda, Masanori Matsumoto, Misako Watanabe, Ayako Takeuchi, Osamu Akira, Shizuo Kato, Nobuyuki Shimotohno, Kunitada Seya, Tsukasa PLoS One Research Article The DEAD box helicase DDX3 assembles IPS-1 (also called Cardif, MAVS, or VISA) in non-infected human cells where minimal amounts of the RIG-I-like receptor (RLR) protein are expressed. DDX3 C-terminal regions directly bind the IPS-1 CARD-like domain as well as the N-terminal hepatitis C virus (HCV) core protein. DDX3 physically binds viral RNA to form IPS-1-containing spots, that are visible by confocal microscopy. HCV polyU/UC induced IPS-1-mediated interferon (IFN)-beta promoter activation, which was augmented by co-transfected DDX3. DDX3 spots localized near the lipid droplets (LDs) where HCV particles were generated. Here, we report that HCV core protein interferes with DDX3-enhanced IPS-1 signaling in HEK293 cells and in hepatocyte Oc cells. Unlike the DEAD box helicases RIG-I and MDA5, DDX3 was constitutively expressed and colocalized with IPS-1 around mitochondria. In hepatocytes (O cells) with the HCV replicon, however, DDX3/IPS-1-enhanced IFN-beta-induction was largely abrogated even when DDX3 was co-expressed. DDX3 spots barely merged with IPS-1, and partly assembled in the HCV core protein located near the LD in O cells, though in some O cells IPS-1 was diminished or disseminated apart from mitochondria. Expression of DDX3 in replicon-negative or core-less replicon-positive cells failed to cause complex formation or LD association. HCV core protein and DDX3 partially colocalized only in replicon-expressing cells. Since the HCV core protein has been reported to promote HCV replication through binding to DDX3, the core protein appears to switch DDX3 from an IFN-inducing mode to an HCV-replication mode. The results enable us to conclude that HCV infection is promoted by modulating the dual function of DDX3. Public Library of Science 2010-12-08 /pmc/articles/PMC2999533/ /pubmed/21170385 http://dx.doi.org/10.1371/journal.pone.0014258 Text en Oshiumi et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Oshiumi, Hiroyuki
Ikeda, Masanori
Matsumoto, Misako
Watanabe, Ayako
Takeuchi, Osamu
Akira, Shizuo
Kato, Nobuyuki
Shimotohno, Kunitada
Seya, Tsukasa
Hepatitis C Virus Core Protein Abrogates the DDX3 Function That Enhances IPS-1-Mediated IFN–Beta Induction
title Hepatitis C Virus Core Protein Abrogates the DDX3 Function That Enhances IPS-1-Mediated IFN–Beta Induction
title_full Hepatitis C Virus Core Protein Abrogates the DDX3 Function That Enhances IPS-1-Mediated IFN–Beta Induction
title_fullStr Hepatitis C Virus Core Protein Abrogates the DDX3 Function That Enhances IPS-1-Mediated IFN–Beta Induction
title_full_unstemmed Hepatitis C Virus Core Protein Abrogates the DDX3 Function That Enhances IPS-1-Mediated IFN–Beta Induction
title_short Hepatitis C Virus Core Protein Abrogates the DDX3 Function That Enhances IPS-1-Mediated IFN–Beta Induction
title_sort hepatitis c virus core protein abrogates the ddx3 function that enhances ips-1-mediated ifn–beta induction
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2999533/
https://www.ncbi.nlm.nih.gov/pubmed/21170385
http://dx.doi.org/10.1371/journal.pone.0014258
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