The experiments described in this proposal will address the translation and RNA replication functions encoded by the 5' non-coding region (5' NCR) of picornavirus genomic RNAs. These functions are the result of protein-protein, RNA-protein, and RNA-RNA interactions involving both viral and cellular components. The proposed experiments will address the roles of viral RNAs and cellular proteins as they pertain to the separate activities of translation initiation and RNA synthesis. However, because there is functional overlap between some of the components utilized during cap-independent translation initiation by picornaviruses encoding type I IRES elements and proteins involved in picornavirus RNA synthesis, some of the proposed experiments will converge on both processes. Experiments outlined in this proposal will define the domains in the cellular RNA-binding protein, poly(rC) binding protein (PCBP2), required for multimerization and/or RNA binding and how such domains contribute to viral functions in the cytoplasm of infected cells. Such experiments will address important mechanistic questions regarding the role of PCBP2 and other cellular polypeptides in picornavirus translation initiation. This proposal will also test a hypothesis posited to explain a putative switch between translation and RNA replication on the same template (or templates) during a picornavirus infectious cycle. Finally, in vivo cell culture experiments are proposed that utilize recently described experimental approaches to modulate protein levels and domain functions of cellular proteins hypothesized to participate in specific steps in the viral life cycle that involve the genomic RNA 5' NCR. Results from these proposed studies will provide new mechanistic insights into the complex processes involved in picornavirus translation initiation and into the interplay between translation functions and viral RNA replication. In addition, data generated from such studies should reveal fundamental aspects of RNA-protein interactions relevant to cellular cap-independent translation as well as pre-mRNA splicing and other elements of RNA metabolism.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Experimental Virology Study Section (EVR)
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Park, Eun-Chung
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University of California Irvine
Schools of Medicine
United States
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Ullmer, Wendy; Semler, Bert L (2018) Direct and Indirect Effects on Viral Translation and RNA Replication Are Required for AUF1 Restriction of Enterovirus Infections in Human Cells. MBio 9:
Lévêque, Nicolas; Garcia, Magali; Bouin, Alexis et al. (2017) Functional Consequences of RNA 5'-Terminal Deletions on Coxsackievirus B3 RNA Replication and Ribonucleoprotein Complex Formation. J Virol 91:
Ullmer, Wendy; Semler, Bert L (2016) Diverse Strategies Used by Picornaviruses to Escape Host RNA Decay Pathways. Viruses 8:
Lévêque, Nicolas; Semler, Bert L (2015) A 21st century perspective of poliovirus replication. PLoS Pathog 11:e1004825
Flather, Dylan; Semler, Bert L (2015) Picornaviruses and nuclear functions: targeting a cellular compartment distinct from the replication site of a positive-strand RNA virus. Front Microbiol 6:594
Tsai, Becky Pinjou; Jimenez, Judith; Lim, Sharon et al. (2014) A novel Bcr-Abl-mTOR-eIF4A axis regulates IRES-mediated translation of LEF-1. Open Biol 4:140180
Chase, Amanda J; Daijogo, Sarah; Semler, Bert L (2014) Inhibition of poliovirus-induced cleavage of cellular protein PCBP2 reduces the levels of viral RNA replication. J Virol 88:3192-201
Chase, Amanda J; Semler, Bert L (2014) Differential cleavage of IRES trans-acting factors (ITAFs) in cells infected by human rhinovirus. Virology 449:35-44
Cathcart, Andrea L; Semler, Bert L (2014) Differential restriction patterns of mRNA decay factor AUF1 during picornavirus infections. J Gen Virol 95:1488-92
Langereis, Martijn A; Feng, Qian; Nelissen, Frank H T et al. (2014) Modification of picornavirus genomic RNA using 'click' chemistry shows that unlinking of the VPg peptide is dispensable for translation and replication of the incoming viral RNA. Nucleic Acids Res 42:2473-82

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