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Invasion and Replication Strategies of Pathogenes
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SP B1

Regulation of Translation in Picornaviruses
and Hepatitis C Virus




Dr. Michael Niepmann
Biochemisches Institut (FB 11), Justus-Liebig-Universität, Gießen
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Summary

The RNA genomes of several positive-strand RNA-viruses can be directly used for translation after infection of a cell. These viruses include the picornaviruses like Poliovirus, Rhinoviruses, Hepatitis A Virus and the animal pathogen Foot-and-Mouth Disease Virus as well as Hepatitis C Virus (HCV). For the preferential translation of their own viral proteins, these viruses bypass the normal route of cap-dependent translation in the eukaryotic cell by a special mechanism. The initiation of translation of viral proteins is directed by a cis-acting region of the viral RNA, the internal ribosome entry site (IRES).

We investigate the interaction of these viral IRES elements with the cellular translation apparatus. The IRES elements of the picornaviruses recruit almost all of the standard eukaryotic translation initiation factors (eIFs) except the Cap-binding protein eIF4E. Moreover, the IRES activity is modulated by other cellular RNA-binding proteins which are not involved in translation of normal cellular mRNAs, like the polypyrimidine tract-binding protein (PTB), the protein encoded upstream of N-ras (Unr) or the heterogeneous nuclear ribonucleoprotein L (hnRNP L). In contrast, the IRES of HCV can bind to the ribosome independently of initiation factors.

Although located at the other end of the genomic RNA, also the 3´-untranslated region (3´-UTR) of HCV is involved in translation regulation. This process is similar to the enhancement of translation of normal cellular mRNAs, which are bound at the Cap-nucleotide at their 5´-end by the initiation factor eIF4F and at their poly(A)-tail at the 3´-end by the Poly(A)-binding protein PABP. The protein-protein interaction of PABP with eIF4F then leads to a circularization of the mRNA which then results in a more efficient (re-) utilization of the ribosomes. Although there is no Cap-nucleotide and no poly(A)-tail on the HCV RNA genome, a similar protein-mediated interaction of the terminal structures of the RNA is assumed to take place also in the process of HCV translation.

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