PI4K-beta and MKNK1 are regulators of hepatitis C virus IRES-dependent translation.
Cellular translation is down-regulated by host antiviral responses. Picornaviridae and Flaviviridae including hepatitis C virus (HCV) evade this process using internal ribosomal entry sequences (IRESs). Although HCV IRES translation is a prerequisite for HCV replication, only few host factors critical for IRES activity are known and the global regulator network remains largely unknown. Since signal transduction is an import regulator of viral infections and the host antiviral response we combined a functional RNAi screen targeting the human signaling network with a HCV IRES-specific reporter mRNA assay. We demonstrate that the HCV host cell cofactors PI4K and MKNK1 are positive regulators of HCV IRES translation representing a novel pathway with a functional relevance for the HCV life cycle and IRES-mediated translation of viral RNA.
Inserm U1110, Institut de Recherche sur les Maladies Virales et Hépatiques Strasbourg, France.|Université de Strasbourg, France.
Joachim
J
Lupberger
Department of Medicine II, University of Freiburg, Freiburg, Germany.
Claudia
C
Casanova
High Throughput Screening platform, IGBMC, UMR7104 CNRS UdS, Inserm, U964, Illkirch, France.
Benoit
B
Fischer
High Throughput Screening platform, IGBMC, UMR7104 CNRS UdS, Inserm, U964, Illkirch, France.
Amelie
A
Weiss
Inserm U1110, Institut de Recherche sur les Maladies Virales et Hépatiques Strasbourg, France.|Université de Strasbourg, France.
Isabel
I
Fofana
Inserm U1110, Institut de Recherche sur les Maladies Virales et Hépatiques Strasbourg, France.|Université de Strasbourg, France.
Nelly
N
Fontaine
Laboratory of Hygienic Chemistry, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
Toshinobu
T
Fujiwara
High Throughput Screening platform, IGBMC, UMR7104 CNRS UdS, Inserm, U964, Illkirch, France.
Mickael
M
Renaud
High Throughput Screening platform, IGBMC, UMR7104 CNRS UdS, Inserm, U964, Illkirch, France.
Arnaud
A
Kopp
Inserm U1110, Institut de Recherche sur les Maladies Virales et Hépatiques Strasbourg, France.|Université de Strasbourg, France.
Catherine
C
Schuster
High Throughput Screening platform, IGBMC, UMR7104 CNRS UdS, Inserm, U964, Illkirch, France.
Laurent
L
Brino
Inserm U1110, Institut de Recherche sur les Maladies Virales et Hépatiques Strasbourg, France.|Université de Strasbourg, France.|Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil, Strasbourg, France.
Thomas F
TF
Baumert
Department of Medicine II, University of Freiburg, Freiburg, Germany.
Christian
C
Thoma
D002460:Cell Line; D002470:Cell Survival; D017930:Genes, Reporter; D016174:Hepacivirus / Q000235:genetics*; D006801:Humans; D000067556:Internal Ribosome Entry Sites / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015778:Minor Histocompatibility Antigens; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D012367:RNA, Viral / Q000235:genetics
D000067556:Internal Ribosome Entry Sites; D047908:Intracellular Signaling Peptides and Proteins; D015778:Minor Histocompatibility Antigens; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012367:RNA, Viral; C491395:MKNK1 protein, human; D017853:Phosphotransferases (Alcohol Group Acceptor); C402182:phosphatidylinositol phosphate 4-kinase; D017346:Protein Serine-Threonine Kinases