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      RNA Binding Protein RBM38 Regulates Expression of the 11-Kilodalton Protein of Parvovirus B19, Which Facilitates Viral DNA Replication

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          ABSTRACT

          Human parvovirus B19 (B19V) expresses a single precursor mRNA (pre-mRNA), which undergoes alternative splicing and alternative polyadenylation to generate 12 viral mRNA transcripts that encode two structural proteins (VP1 and VP2) and three nonstructural proteins (NS1, 7.5-kDa protein, and 11-kDa protein). Splicing at the second 5′ donor site (D2 site) of the B19V pre-mRNA is essential for the expression of VP2 and the 11-kDa protein. We previously identified that cis-acting intronic splicing enhancer 2 (ISE2) that lies immediately after the D2 site facilitates the recognition of the D2 donor for its efficient splicing. In this study, we report that ISE2 is critical for the expression of the 11-kDa viral nonstructural protein. We found that ISE2 harbors a consensus RNA binding motif protein 38 (RBM38) binding sequence, 5′-UGUGUG-3′. RBM38 is expressed during the middle stage of erythropoiesis. We first confirmed that RBM38 binds specifically with the ISE2 element in vitro. The knockdown of RBM38 significantly decreases the level of spliced mRNA at D2 that encodes the 11-kDa protein but not that of the D2-spliced mRNA that encodes VP2. Importantly, we found that the 11-kDa protein enhances viral DNA replication and virion release. Accordingly, the knockdown of RBM38 decreases virus replication via downregulating 11-kDa protein expression. Taken together, these results suggest that the 11-kDa protein facilitates B19V DNA replication and that RBM38 is an essential host factor for B19V pre-mRNA splicing and for the expression of the 11-kDa protein.

          IMPORTANCE B19V is a human pathogen that can cause fifth disease, arthropathy, anemia in immunocompromised patients and sickle cell disease patients, myocarditis, and hydrops fetalis in pregnant women. Human erythroid progenitor cells (EPCs) are most susceptible to B19V infection and fully support viral DNA replication. The exclusive tropism of B19V for erythroid-lineage cells is dependent not only on the expression of viral receptors and coreceptors on the cell surface but also on the intracellular host factors that support B19V replication. Our present study shows that B19V uses a host factor, RNA binding motif protein 38 (RBM38), for the processing of its pre-mRNA during virus replication. Specifically, RBM38 interacts with the intronic splicing enhancer 2 (ISE2) element of B19V pre-mRNA and promotes 11-kDa protein expression, thereby regulating the 11-kDa protein-mediated augmentation of B19V replication. The identification of this novel host-pathogen interaction will provide mechanistic insights into B19V replication and aid in finding new targets for anti-B19V therapeutics.

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          Author and article information

          Contributors
          Role: Editor
          Journal
          J Virol
          J. Virol
          jvi
          jvi
          JVI
          Journal of Virology
          American Society for Microbiology (1752 N St., N.W., Washington, DC )
          0022-538X
          1098-5514
          7 February 2018
          28 March 2018
          15 April 2018
          : 92
          : 8
          : e02050-17
          Affiliations
          [a ]Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, Kansas, USA
          [b ]Institute of Preventive Veterinary Medicine, Zhejiang Provincial Key Laboratory of Preventive Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou, China
          [c ]Department of Research and Development, Viracor Eurofins Laboratories, Lee's Summit, Missouri, USA
          University of Southern California
          Author notes
          Address correspondence to Jianming Qiu, jqiu@ 123456kumc.edu .

          Citation Ganaie SS, Chen AY, Huang C, Xu P, Kleiboeker S, Du A, Qiu J. 2018. RNA binding protein RBM38 regulates expression of the 11-kilodalton protein of parvovirus B19, which facilitates viral DNA replication. J Virol 92:e02050-17. https://doi.org/10.1128/JVI.02050-17.

          Article
          PMC5874399 PMC5874399 5874399 02050-17
          10.1128/JVI.02050-17
          5874399
          29437973
          2f62013e-d852-4bff-93c7-92d62c2f56e0
          Copyright © 2018 American Society for Microbiology.

          All Rights Reserved.

          History
          : 28 November 2017
          : 1 February 2018
          Page count
          Figures: 9, Tables: 0, Equations: 0, References: 56, Pages: 17, Words: 9658
          Funding
          Funded by: HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID), https://doi.org/10.13039/100000060;
          Award ID: AI070723
          Award Recipient :
          Categories
          Genome Replication and Regulation of Viral Gene Expression
          Custom metadata
          April 2018

          mRNA splicing,B19,parvovirus
          mRNA splicing, B19, parvovirus

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