Translation of Hepatitis A Virus IRES Is Upregulated by a Hepatic Cell-Specific Factor

  • Sadahiro, Akitoshi
    Laboratory of Infection and Prevention, Department of Virus Research, Institute for Frontier Life and Medical Sciences, Kyoto University
  • Fukao, Akira
    Laboratory of Biochemistry, Graduate School of Pharmaceutical Sciences, Kindai University
  • Kosaka, Mio
    Laboratory of Biochemistry, Graduate School of Pharmaceutical Sciences, Kindai University
  • Funakami, Yoshinori
    Laboratory of Biochemistry, Graduate School of Pharmaceutical Sciences, Kindai University
  • Takizawa, Naoki
    Laboratory of Virology, Institute of Microbial Chemistry (BIKAKEN)
  • Takeuchi, Osamu
    Laboratory of Infection and Prevention, Department of Virus Research, Institute for Frontier Life and Medical Sciences, Kyoto University
  • Duncan, Kent E.
    Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf
  • Fujiwara, Toshinobu
    Laboratory of Biochemistry, Graduate School of Pharmaceutical Sciences, Kindai University

Abstract

Many viruses strongly prefer to infect certain cell types, a phenomenon known as “tropism.” Understanding tropism’s molecular basis is important for the design of vaccines and antiviral therapy. A common mechanism involves viral protein interactions with cell-specific surface receptors, but intracellular mechanisms involving translation have also been described. In this report, we focus on Hepatitis A Virus (HAV) tissue tropism from the standpoint of the translational machinery. HAV genomic RNA, like other positive stranded RNA viruses, is devoid of a cap structure and its translation is driven by highly structured RNA sequences termed internal ribosome entry site (IRES) in the 5′ untranslated region (UTR). Unlike most viral IRESs, HAV IRES-mediated translation requires eIF4E and the 3′ end of HAV RNA is polyadenylated. However, the molecular mechanism of HAV IRES-mediated translation initiation remains poorly understood. We analyzed HAV-IRES-mediated translation in a cell-free system derived from either non-hepatic cells (HeLa) or hepatoma cells (Huh-7) that enables investigation of the contribution of the cap and the poly(A) tail. This revealed that HAV IRES-mediated translation activity in hepatoma cell extracts is higher as compared to extracts derived from a non-hepatic line. Our data suggest that HAV IRES-mediated translation is upregulated by a hepatic cell-specific activator in a poly(A) tail-independent manner.

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