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REVIEW: Non-Canonical Translation Initiation Mechanisms Employed by Eukaryotic Viral mRNAs

Ivan I. Sorokin1,2,3, Konstantin S. Vassilenko2, Ilya M. Terenin1, Natalia O. Kalinina1,4, Vadim I. Agol1,5, and Sergey E. Dmitriev1,6,7a,*

1Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119234 Moscow, Russia

2Institute of Protein Research, Russian Academy of Sciences, 142290 Pushchino, Moscow Region, Russia

3Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Moscow Region, Russia

4Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia

5Institute of Poliomyelitis, Chumakov Center for Research and Development of Immunobiological Products, Russian Academy of Sciences, 108819 Moscow, Russia

6Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia

7Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119234 Moscow, Russia

* To whom correspondence should be addressed.

Received June 14, 2021; Revised August 4, 2021; Accepted August 4, 2021
Viruses exploit the translation machinery of an infected cell to synthesize their proteins. Therefore, viral mRNAs have to compete for ribosomes and translation factors with cellular mRNAs. To succeed, eukaryotic viruses adopt multiple strategies. One is to circumvent the need for m7G-cap through alternative instruments for ribosome recruitment. These include internal ribosome entry sites (IRESs), which make translation independent of the free 5′ end, or cap-independent translational enhancers (CITEs), which promote initiation at the uncapped 5′ end, even if located in 3′ untranslated regions (3′ UTRs). Even if a virus uses the canonical cap-dependent ribosome recruitment, it can still perturb conventional ribosomal scanning and start codon selection. The pressure for genome compression often gives rise to internal and overlapping open reading frames. Their translation is initiated through specific mechanisms, such as leaky scanning, 43S sliding, shunting, or coupled termination-reinitiation. Deviations from the canonical initiation reduce the dependence of viral mRNAs on translation initiation factors, thereby providing resistance to antiviral mechanisms and cellular stress responses. Moreover, viruses can gain advantage in a competition for the translational machinery by inactivating individual translational factors and/or replacing them with viral counterparts. Certain viruses even create specialized intracellular “translation factories”, which spatially isolate the sites of their protein synthesis from cellular antiviral systems, and increase availability of translational components. However, these virus-specific mechanisms may become the Achilles’ heel of a viral life cycle. Thus, better understanding of the unconventional mechanisms of viral mRNA translation initiation provides valuable insight for developing new approaches to antiviral therapy.
KEY WORDS: cap-independent translation, VPg, IRES and 3′ CITE, TURBS-mediated reinitiation, circular RNAs, translation initiation factors eIF2 and eIF4F, picornaviruses PV and EMCV, flaviviruses HCV and DENV, lentiviruses HIV-1 and HIV-2, coronavirus SARS-CoV-2

DOI: 10.1134/S0006297921090042