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3264.Full.Pdf Melanoma Differentiation−Associated Gene 5 Senses Hepatitis B Virus and Activates Innate Immune Signaling To Suppress Virus Replication This information is current as of September 23, 2021. Hsin-Lin Lu and Fang Liao J Immunol 2013; 191:3264-3276; Prepublished online 7 August 2013; doi: 10.4049/jimmunol.1300512 http://www.jimmunol.org/content/191/6/3264 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2013/08/07/jimmunol.130051 Material 2.DC1 http://www.jimmunol.org/ References This article cites 68 articles, 24 of which you can access for free at: http://www.jimmunol.org/content/191/6/3264.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 23, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Melanoma Differentiation–Associated Gene 5 Senses Hepatitis B Virus and Activates Innate Immune Signaling To Suppress Virus Replication Hsin-Lin Lu* and Fang Liao*,† Retinoic acid–inducible gene-I (RIG-I) and melanoma differentiation–associated gene 5 (MDA5) belong to the RIG-I–like recep- tors family of pattern recognition receptors. Both RIG-I and MDA5 have been shown to recognize various viral RNAs, but whether they mediate hepatitis B virus (HBV) infection remains unclear. In this study, we demonstrated that the expression of MDA5,butnotRIG-I, was increased in Huh7 cells transfected with the HBV replicative plasmid and in the livers of mice hydrodynamically injected with the HBV replicative plasmid. To further determine the effect of RIG-I–like receptors on HBV replication, we cotransfected the HBV replicative plasmid with RIG-I or MDA5 expression plasmid into Huh7 cells and found that Downloaded from MDA5, but not RIG-I at a similar protein level, significantly inhibited HBV replication. Knockdown of endogenous MDA5, but not RIG-I, in Huh7 cells transfected with the HBV replicative plasmid significantly increased HBV replication. Of particular interest, we found that MDA5, but not RIG-I, was able to associate with HBV-specific nucleic acids, suggesting that MDA5 may sense HBV. Finally, we performed in vivo experiments by hydrodynamic injection of the HBV replicative plasmid into wild-type, MDA52/2, MDA5+/2,orRIG-I+/2 mice, and found that MDA52/2 and MDA5+/2 mice, but not RIG-I+/2 mice, exhibited an increase of HBV replication as compared with wild-type mice. Collectively, our in vitro and in vivo studies both support a critical role for MDA5 in http://www.jimmunol.org/ the innate immune response against HBV infection. The Journal of Immunology, 2013, 191: 3264–3276. uman hepatitis B virus (HBV) is a small (3.2-kb), en- RNAs, which are exported to the cytoplasm and used as mRNA veloped, noncytopathic DNA virus characterized by for translating HBV proteins. The largest viral RNA (3.5 kb), H its pronounced species and liver tropism (1). HBV in- known as the viral pregenomic RNA (pgRNA), is assembled with fection is worldwide with a high prevalence in Asia and Africa, HBV polymerase and core proteins to form nucleocapsids, and and it causes a wide spectrum of liver diseases, including acute/ functions as the template for reverse transcription within nucleo- chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma capsids in the cytoplasm, ultimately generating newly synthesized (1, 2). Although HBV vaccine has been available for three deca- rcDNA. The nucleocapsids can be either enveloped during their by guest on September 23, 2021 des, the innate immune response to HBV infection remains to be passage through the endoplasmic reticulum and Golgi complex elucidated. followed by secretion from the cells or retransported into the The genomic arrangement of HBV is unique among viruses. The nucleus for the amplification of the cccDNA pool to generate more HBV genome comprises a relaxed circular partially dsDNA that viral RNAs (1, 2). contains four overlapping reading frames encoding the enve- Hosts infected by viruses usually elicit a rapid and potent in- lope, precore/core, polymerase, and X proteins (2). After entry and nate immune response to produce antiviral molecules to limit viral uncoating of HBV in hepatocytes, the HBV genome is transported replication and to prevent viral spreading before the adaptive into the nucleus, and the relaxed circular DNA (rcDNA) is con- immune response is generated (3–5). Pattern recognition receptors verted into covalently closed circular DNA (cccDNA). The cccDNA (PRRs), which recognize various pathogen-associated molecule serves as a transcriptional template for the synthesis of four viral patterns, have been shown to play a critical role in the innate im- mune response against pathogens (6). Among PRRs, the endo- somal TLRs including TLR3, TLR7/8, and TLR9, and cytosolic *Institute of Microbiology and Immunology, National Yang-Ming University, Taipei RIG-I–like receptors (RLRs) including retinoic acid–inducible † 11221, Taiwan; and Institute of Biomedical Sciences, Academia Sinica, Taipei gene I (RIG-I) and melanoma differentiation–associated gene 5 11529, Taiwan (MDA5) are important for sensing viral RNA during viral infec- Received for publication February 21, 2013. Accepted for publication July 5, 2013. tion (3, 5, 6). After the recognition of virus-associated molecules This work was supported by grants from Academia Sinica in Taiwan. by PRRs, PRRs activate their specific adaptor proteins: TIR Address correspondence and reprint requests to Dr. Fang Liao, Institute of Biomed- domain-containing adapter-inducing IFN-b for TLR3 (7), MyD88 ical Sciences, Academia Sinica, Taipei 11529, Taiwan. E-mail address: fl9z@ibms. b sinica.edu.tw for TLR7/8 and TLR9 (8), and IFN- promoter stimulator 1(IPS- The online version of this article contains supplemental material. 1), also known as mitochondrial antiviral signaling protein, CARD adaptor-inducing IFN-b, and virus-induced signaling adaptor for Abbreviations used in this article: cccDNA, covalently closed circular DNA; DP, deproteinized; HBcAg, HBV core Ag; HBsAg, HBV surface Ag; HBV, hepatitis B RLRs (9–12). The activation of adaptor proteins of PRRs ultimately virus; IPS-1, IFN-b promoter stimulator 1; IRF, IFN regulatory factor; ISG, IFN- activates downstream transcription factors, IFN regulatory factors stimulated gene; MDA5, melanoma differentiation–associated gene 5; NP-40, Non- k idet P-40; PARP, poly(ADP-ribose) polymerase; pgRNA, pregenomic RNA; PRR, (IRFs), and NF- B, to induce genes that are critical for antiviral pattern recognition receptor; rcDNA, relaxed circular DNA; RIG-I, retinoic acid– functions, as well as the dictation of adaptive immune responses inducible gene-I; RLR, RIG-I–like receptor; siRNA, small interfering RNA; TMB, (3, 5, 6). The inhibition of HBV replication and the induction tetramethylbenzidine; VSV, vesicular stomatitis virus. of antiviral effects by TLR signaling are primarily mediated by Copyright Ó 2013 by The American Association of Immunologists, Inc. 0022-1767/13/$16.00 nonparenchymal cells, such as dendritic cells, Kupffer cells, and www.jimmunol.org/cgi/doi/10.4049/jimmunol.1300512 The Journal of Immunology 3265 liver sinusoidal endothelial cells (13, 14). Given that TLRs are Committee at Academia Sinica and were performed in accordance with expressed on plasma or endosomal membranes to recognize institutional guidelines. ligands from extracellular compartments, and that HBV is a non- Cell culture cytopathic DNA virus whose nucleic acids may not be present in extracellular compartments, one would expect that TLR signaling Huh7 cells were cultured in DMEM supplemented with 10% FBS (Life Technologies, Grand Island, NY), 2 mM L-glutamine, 1% nonessential may not be so critical for the innate response to HBV in hep- amino acids, and 1% sodium pyruvate (Life Technologies) at 37˚C under atocytes. Because RLRs are cytosolic viral sensors and HBV 5% CO2 in a humidified atmosphere. nucleic acids may be present in the cytosol in addition to the Plasmids nucleus as described in the aforementioned paragraph, HBV is more likely to be recognized by RLRs. Consistent with this no- The pSV2ANeo-HBVx2 plasmid, an HBV ayw dimer DNA containing tion, recent studies have demonstrated that overexpression of IPS- plasmid that has two head-to-tail copies of the HBV genome of ayw 1 in a hepatoma cell line transfected with the HBV replicative subtype (33), and the polymerase-null HBV mutant 2310, a point mutation converting the first ATG codon of HBV pol at nucleotide 2310 into ACG in plasmid significantly suppresses HBV replication (15), and that pSV2ANeo-HBVx2 plasmid (34, 35), were kindly provided by Dr. Chiaho HBV X protein interacts with IPS-1 and disrupts the downstream Shih (Institute of Biomedical Sciences, Academia Sinica). To generate pKRX- signaling of RLRs to prevent the production of type I IFNs in- HBVx2, we subjected pSV2ANeo-HBVx2 to EcoRI partial digestion to duced by Sendai virus, vesicular stomatitis virus (VSV), or poly obtain the HBV dimer DNA fragment of HBV ayw subtype, which was then subcloned into the pKRX vector at the EcoRI site. To construct (dA:dT) (16–19). Furthermore, two studies have shown that HBV pCAGGS-RIG-I-Flag2, we used pEF-BOS-RIG-I plasmid (provided by pol impairs the activation of TBK1/IKKε, the downstream sig- Dr. Takashi Fujita, Department of Molecular Genetics, Institute for Virus naling molecule of IPS-1 in the RLR signaling pathway (20, 21).
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