NOD1 Participates in the Innate Immune Response Triggered by Hepatitis C Virus Polymerase.
Hepatitis C virus (HCV) triggers innate immunity signaling in the infected cell. Replication of the viral genome is dispensable for this phenotype, and we along with others have recently shown that NS5B, the viral RNA-dependent RNA polymerase, synthesizes double-stranded RNA (dsRNA) from cellular templates, thus eliciting an inflammatory response, notably via activation of type I interferon and lymphotoxin β. Here, we investigated intracellular signal transduction pathways involved in this process. Using HepaRG cells, a model that largely recapitulates the in vivo complexities of the innate immunity receptor signaling, we have confirmed that NS5B triggered increased expression of the canonical pattern recognition receptors (PRRs) specific for dsRNA, namely, RIG-I, MDA5, and Toll-like receptor 3 (TLR3). Unexpectedly, intracellular dsRNA also led to accumulation of NOD1, a receptor classically involved in recognition of bacterial peptidoglycans. NOD1 activation, confirmed by analysis of its downstream targets, was likely due to its interaction with dsRNA and was independent of RIG-I and mitochondrial antiviral signaling protein (MAVS/IPS-1/Cardif/VISA) signaling. It is likely to have a functional significance in the cellular response in the context of HCV infection since interference with the NOD1 pathway severely reduced the inflammatory response elicited by NS5B.



In this study, we show that NOD1, a PRR that normally senses bacterial peptidoglycans, is activated by HCV viral polymerase, probably through an interaction with dsRNA, suggesting that NOD1 acts as an RNA ligand recognition receptor. In consequence, interference with NOD1-mediated signaling significantly weakens the inflammatory response to dsRNA. These results add a new level of complexity to the understanding of the cross talk between different classes of pattern recognition receptors and may be related to certain complications of chronic hepatitis C virus infection.
CNRS, UMR 5535, Institut de Génétique Moléculaire de Montpellier, Montpellier, France.|Université de Montpellier, Montpellier, France.
Serena
S
Vegna
CNRS, UMR 5535, Institut de Génétique Moléculaire de Montpellier, Montpellier, France.|Université de Montpellier, Montpellier, France.
Damien
D
Gregoire
CNRS, UMR 5535, Institut de Génétique Moléculaire de Montpellier, Montpellier, France.|Université de Montpellier, Montpellier, France.
Marie
M
Moreau
CNRS, UMR 5535, Institut de Génétique Moléculaire de Montpellier, Montpellier, France.|Université de Montpellier, Montpellier, France.
Patrice
P
Lassus
INSERM, U1052, Cancer Research Center of Lyon, University of Lyon, Lyon, France.
David
D
Durantel
CNRS, UMR 5535, Institut de Génétique Moléculaire de Montpellier, Montpellier, France.|Université de Montpellier, Montpellier, France.|Service d'Oncologie Médicale, CHU St. Eloi, Montpellier, France.
Eric
E
Assenat
CNRS, UMR 5535, Institut de Génétique Moléculaire de Montpellier, Montpellier, France.|Université de Montpellier, Montpellier, France.
Urszula
U
Hibner
CNRS, UMR 5535, Institut de Génétique Moléculaire de Montpellier, Montpellier, France yannick.simonin@umontpellier.fr.|Université de Montpellier, Montpellier, France.
Yannick
Y
Simonin
D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D000071457:DEAD Box Protein 58 / Q000235:genetics / Q000378:metabolism; D016174:Hepacivirus / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D022781:Hepatocytes / Q000821:virology; D006801:Humans; D007113:Immunity, Innate; D000072640:Interferon-Induced Helicase, IFIH1 / Q000235:genetics / Q000378:metabolism; D053474:Nod1 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D012330:RNA, Double-Stranded / Q000276:immunology / Q000378:metabolism*; D012324:RNA-Dependent RNA Polymerase / Q000235:genetics / Q000378:metabolism*; D011971:Receptors, Immunologic; D051192:Receptors, Pattern Recognition / Q000378:metabolism*; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism*
C119067:NOD1 protein, human; D053474:Nod1 Signaling Adaptor Protein; D012330:RNA, Double-Stranded; D011971:Receptors, Immunologic; D051192:Receptors, Pattern Recognition; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C452820:RIGI protein, human; C452815:IFIH1 protein, human; D000071457:DEAD Box Protein 58; D000072640:Interferon-Induced Helicase, IFIH1