Various miRNAs compensate the role of miR-122 on HCV replication

Autoři: Chikako Ono aff001;  Takasuke Fukuhara aff001;  Songling Li aff002;  Jian Wang aff003;  Asuka Sato aff001;  Takuma Izumi aff001;  Yuzy Fauzyah aff001;  Takuya Yamamoto aff001;  Yuhei Morioka aff001;  Nikolay V. Dokholyan aff003;  Daron M. Standley aff002;  Yoshiharu Matsuura aff001
Působiště autorů: Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan aff001;  Department of Genome Informatics, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan aff002;  Department of Pharmacology, Penn State University College of Medicine, Hershey, Pennsylvania, United States of America aff003;  Department of Biochemistry & Molecular Biology, Penn State University College of Medicine, Hershey, Pennsylvania, United States of America aff004
Vyšlo v časopise: Various miRNAs compensate the role of miR-122 on HCV replication. PLoS Pathog 16(6): e32767. doi:10.1371/journal.ppat.1008308
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008308


One of the determinants for tissue tropism of hepatitis C virus (HCV) is miR-122, a liver-specific microRNA. Recently, it has been reported that interaction of miR-122 to HCV RNA induces a conformational change of the 5’UTR internal ribosome entry site (IRES) structure to form stem-loop II structure (SLII) and hijack of translating 80S ribosome through the binding of SLIII to 40S subunit, which leads to efficient translation. On the other hand, low levels of HCV-RNA replication have also been detected in some non-hepatic cells; however, the details of extrahepatic replication remain unknown. These observations suggest the possibility that miRNAs other than miR-122 can support efficient replication of HCV-RNA in non-hepatic cells. Here, we identified a number of such miRNAs and show that they could be divided into two groups: those that bind HCV-RNA at two locations (miR-122 binding sites I and II), in a manner similar to miR-122 (miR-122-like), and those that target a single site that bridges sites I and II and masking both G28 and C29 in the 5’UTR (non-miR-122-like). Although the enhancing activity of these non-hepatic miRNAs were lower than those of miR-122, substantial expression was detected in various normal tissues. Furthermore, structural modeling indicated that both miR-122-like and non-miR-122-like miRNAs not only can facilitate the formation of an HCV IRES SLII but also can stabilize IRES 3D structure in order to facilitate binding of SLIII to the ribosome. Together, these results suggest that HCV facilitates miR-122-independent replication in non-hepatic cells through recruitment of miRNAs other than miR-122. And our findings can provide a more detailed mechanism of miR-122-dependent enhancement of HCV-RNA translation by focusing on IRES tertiary structure.

Klíčová slova:

Hepatitis C virus – Internal ribosome entry site – Luciferase – MicroRNAs – Protein translation – RNA structure – Sequence motif analysis – Viral replication


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