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The Host Factor AUF1 p45 Supports Flavivirus Propagation by Triggering the RNA Switch Required for Viral Genome Cyclization.
J Virol. 2018 03 15; 92(6)JV

Abstract

In previous studies, we showed that the cellular RNA-binding protein AUF1 supports the replication process of the flavivirus West Nile virus. Here we demonstrate that the protein also enables effective proliferation of dengue virus and Zika virus, indicating that AUF1 is a general flavivirus host factor. Further studies demonstrated that the AUF1 isoform p45 significantly stimulates the initiation of viral RNA replication and that the protein's RNA chaperone activity enhances the interactions of the viral 5'UAR and 3'UAR genome cyclization sequences. Most interestingly, we observed that AUF1 p45 destabilizes not only the 3'-terminal stem-loop (3'SL) but also 5'-terminal stem-loop B (SLB) of the viral genome. RNA structure analyses revealed that AUF1 p45 increases the accessibility of defined nucleotides within the 3'SL and SLB and, in this way, exposes both UAR cyclization elements. Conversely, AUF1 p45 does not modulate the fold of stem-loop A (SLA) at the immediate genomic 5' end, which is proposed to function as a promoter of the viral RNA-dependent RNA polymerase (RdRp). These findings suggest that AUF1 p45, by destabilizing specific stem-loop structures within the 5' and 3' ends of the flaviviral genome, assists genome cyclization and concurrently enables the RdRp to initiate RNA synthesis. Our study thus highlights the role of a cellular RNA-binding protein inducing a flaviviral RNA switch that is crucial for viral replication.IMPORTANCE The genus Flavivirus within the Flaviviridae family includes important human pathogens, such as dengue, West Nile, and Zika viruses. The initiation of replication of the flaviviral RNA genome requires a transformation from a linear to a cyclized form. This involves considerable structural reorganization of several RNA motifs at the genomic 5' and 3' ends. Specifically, it needs a melting of stem structures to expose complementary 5' and 3' cyclization elements to enable their annealing during cyclization. Here we show that a cellular RNA chaperone, AUF1 p45, which supports the replication of all three aforementioned flaviviruses, specifically rearranges stem structures at both ends of the viral genome and in this way permits 5'-3' interactions of cyclization elements. Thus, AUF1 p45 triggers the RNA switch in the flaviviral genome that is crucial for viral replication. These findings represent an important example of how cellular (host) factors promote the propagation of RNA viruses.

Authors+Show Affiliations

Institute of Biochemistry and Biotechnology, Martin Luther University Halle-Wittenberg, Halle, Germany susann.friedrich@biochemtech.uni-halle.de sven.behrens@biochemtech.uni-halle.de.Institute of Biochemistry and Biotechnology, Martin Luther University Halle-Wittenberg, Halle, Germany.Institute of Biochemistry and Biotechnology, Martin Luther University Halle-Wittenberg, Halle, Germany.Institute of Virology, Leipzig University, Leipzig, Germany.Institute of Virology, Leipzig University, Leipzig, Germany.Institute of Virology, Leipzig University, Leipzig, Germany.Institute of Virology, University of Bonn Medical Centre, Bonn, Germany.Institute of Biochemistry and Biotechnology, Martin Luther University Halle-Wittenberg, Halle, Germany.Institute of Biochemistry and Biotechnology, Martin Luther University Halle-Wittenberg, Halle, Germany susann.friedrich@biochemtech.uni-halle.de sven.behrens@biochemtech.uni-halle.de.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29263261

Citation

Friedrich, Susann, et al. "The Host Factor AUF1 P45 Supports Flavivirus Propagation By Triggering the RNA Switch Required for Viral Genome Cyclization." Journal of Virology, vol. 92, no. 6, 2018.
Friedrich S, Engelmann S, Schmidt T, et al. The Host Factor AUF1 p45 Supports Flavivirus Propagation by Triggering the RNA Switch Required for Viral Genome Cyclization. J Virol. 2018;92(6).
Friedrich, S., Engelmann, S., Schmidt, T., Szczepankiewicz, G., Bergs, S., Liebert, U. G., Kümmerer, B. M., Golbik, R. P., & Behrens, S. E. (2018). The Host Factor AUF1 p45 Supports Flavivirus Propagation by Triggering the RNA Switch Required for Viral Genome Cyclization. Journal of Virology, 92(6). https://doi.org/10.1128/JVI.01647-17
Friedrich S, et al. The Host Factor AUF1 P45 Supports Flavivirus Propagation By Triggering the RNA Switch Required for Viral Genome Cyclization. J Virol. 2018 03 15;92(6) PubMed PMID: 29263261.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The Host Factor AUF1 p45 Supports Flavivirus Propagation by Triggering the RNA Switch Required for Viral Genome Cyclization. AU - Friedrich,Susann, AU - Engelmann,Susanne, AU - Schmidt,Tobias, AU - Szczepankiewicz,Grit, AU - Bergs,Sandra, AU - Liebert,Uwe G, AU - Kümmerer,Beate M, AU - Golbik,Ralph P, AU - Behrens,Sven-Erik, Y1 - 2018/02/26/ PY - 2017/09/18/received PY - 2017/12/12/accepted PY - 2017/12/22/pubmed PY - 2018/4/12/medline PY - 2017/12/22/entrez KW - AUF1 KW - RNA chaperone KW - RNA cyclization KW - RNA replication KW - RNA-protein interaction KW - West Nile virus KW - Zika virus KW - dengue virus KW - flavivirus KW - host factor JF - Journal of virology JO - J. Virol. VL - 92 IS - 6 N2 - In previous studies, we showed that the cellular RNA-binding protein AUF1 supports the replication process of the flavivirus West Nile virus. Here we demonstrate that the protein also enables effective proliferation of dengue virus and Zika virus, indicating that AUF1 is a general flavivirus host factor. Further studies demonstrated that the AUF1 isoform p45 significantly stimulates the initiation of viral RNA replication and that the protein's RNA chaperone activity enhances the interactions of the viral 5'UAR and 3'UAR genome cyclization sequences. Most interestingly, we observed that AUF1 p45 destabilizes not only the 3'-terminal stem-loop (3'SL) but also 5'-terminal stem-loop B (SLB) of the viral genome. RNA structure analyses revealed that AUF1 p45 increases the accessibility of defined nucleotides within the 3'SL and SLB and, in this way, exposes both UAR cyclization elements. Conversely, AUF1 p45 does not modulate the fold of stem-loop A (SLA) at the immediate genomic 5' end, which is proposed to function as a promoter of the viral RNA-dependent RNA polymerase (RdRp). These findings suggest that AUF1 p45, by destabilizing specific stem-loop structures within the 5' and 3' ends of the flaviviral genome, assists genome cyclization and concurrently enables the RdRp to initiate RNA synthesis. Our study thus highlights the role of a cellular RNA-binding protein inducing a flaviviral RNA switch that is crucial for viral replication.IMPORTANCE The genus Flavivirus within the Flaviviridae family includes important human pathogens, such as dengue, West Nile, and Zika viruses. The initiation of replication of the flaviviral RNA genome requires a transformation from a linear to a cyclized form. This involves considerable structural reorganization of several RNA motifs at the genomic 5' and 3' ends. Specifically, it needs a melting of stem structures to expose complementary 5' and 3' cyclization elements to enable their annealing during cyclization. Here we show that a cellular RNA chaperone, AUF1 p45, which supports the replication of all three aforementioned flaviviruses, specifically rearranges stem structures at both ends of the viral genome and in this way permits 5'-3' interactions of cyclization elements. Thus, AUF1 p45 triggers the RNA switch in the flaviviral genome that is crucial for viral replication. These findings represent an important example of how cellular (host) factors promote the propagation of RNA viruses. SN - 1098-5514 UR - https://www.unboundmedicine.com/medline/citation/29263261/The_Host_Factor_AUF1_p45_Supports_Flavivirus_Propagation_by_Triggering_the_RNA_Switch_Required_for_Viral_Genome_Cyclization_ L2 - https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/29263261/ DB - PRIME DP - Unbound Medicine ER -