title: Cyclosporin A associated helicase-like protein facilitates the association of hepatitis C virus RNA polymerase with its cellular cyclophilin B.
abstract: BACKGROUND
  Cyclosporin A (CsA) is well known as an immunosuppressive drug useful for allogeneic transplantation. It has been reported that CsA inhibits hepatitis C virus (HCV) genome replication, which indicates that cellular targets of CsA regulate the viral replication. However, the regulation mechanisms of HCV replication governed by CsA target proteins have not been fully understood.
  
  
  RESULTS
  Here we show a chemical biology approach that elucidates a novel mechanism of HCV replication. We developed a phage display screening to investigate compound-peptide interaction and identified a novel cellular target molecule of CsA. This protein, named CsA associated helicase-like protein (CAHL), possessed RNA-dependent ATPase activity that was negated by treatment with CsA. The downregulation of CAHL in the cells resulted in a decrease of HCV genome replication. CAHL formed a complex with HCV-derived RNA polymerase NS5B and host-derived cyclophilin B (CyPB), known as a cellular cofactor for HCV replication, to regulate NS5B-CyPB interaction.
  
  
  CONCLUSIONS
  We found a cellular factor, CAHL, as CsA associated helicase-like protein, which would form trimer complex with CyPB and NS5B of HCV. The strategy using a chemical compound and identifying its target molecule by our phage display analysis is useful to reveal a novel mechanism underlying cellular and viral physiology.
authors.affiliation: Genome and Drug Research Center, Tokyo University of Science, Noda, Chiba, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Morohashi
authors.forename: Hiroeki
authors.initials: H
authors.lastname: Sahara
authors.forename: Koichi
authors.initials: K
authors.lastname: Watashi
authors.forename: Kazuki
authors.initials: K
authors.lastname: Iwabata
authors.forename: Takashi
authors.initials: T
authors.lastname: Sunoki
authors.forename: Kouji
authors.initials: K
authors.lastname: Kuramochi
authors.forename: Kaori
authors.initials: K
authors.lastname: Takakusagi
authors.forename: Hiroki
authors.initials: H
authors.lastname: Miyashita
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Sato
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tanabe
authors.forename: Kunitada
authors.initials: K
authors.lastname: Shimotohno
authors.forename: Susumu
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Kengo
authors.initials: K
authors.lastname: Sakaguchi
authors.forename: Fumio
authors.initials: F
authors.lastname: Sugawara
mesh_terms: D000251:Adenosine Triphosphatases / Q000096:biosynthesis* / Q000737:chemistry / Q000502:physiology; D045744:Cell Line, Tumor; D021983:Cyclophilins / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology*; D018076:DNA, Complementary / Q000378:metabolism; D012321:DNA-Directed RNA Polymerases / Q000378:metabolism*; D016174:Hepacivirus / Q000235:genetics*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D019151:Peptide Library; D010957:Plasmids / Q000378:metabolism; D020365:RNA Helicases; D012367:RNA, Viral / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry; D020349:Surface Plasmon Resonance; D014018:Tissue Distribution
chemical_list: D018076:DNA, Complementary; D007166:Immunosuppressive Agents; D019151:Peptide Library; D012367:RNA, Viral; D011994:Recombinant Proteins; C081786:cyclophilin B; D016572:Cyclosporine; D012321:DNA-Directed RNA Polymerases; D000251:Adenosine Triphosphatases; D020365:RNA Helicases; C562343:YTHDC2 protein, human; D021983:Cyclophilins