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Zika virus noncoding sfRNAs sequester multiple host-derived RNA-binding proteins and modulate mRNA decay and splicing during infection.

Abstract

Insect-borne flaviviruses produce a 300-500 base long noncoding RNA, termed subgenomic flavivirus RNA (sfRNA), by stalling the cellular 5'-3' exoribonuclease 1 (XRN1) via structures located in their 3' UTRs. In this study, we demonstrate that sfRNA production by Zika virus represses XRN1 analogous to what we have previously shown for other flaviviruses. Using protein-RNA reconstitution and a stringent RNA pulldown assay with human choriocarcinoma (JAR) cells, we demonstrate that the sfRNAs from both dengue type 2 and Zika viruses interact with a common set of 21 RNA-binding proteins that contribute to the regulation of post-transcriptional processes in the cell, including splicing, RNA stability and translation. We found that four of these sfRNA-interacting host proteins - DEAD-box helicase 6 (DDX6) and enhancer of mRNA decapping 3 (EDC3) (two RNA decay factors), phosphorylated adaptor for RNA export (PHAX, a regulator of the biogenesis of the splicing machinery), and apolipoprotein B mRNA-editing enzyme catalytic subunit 3C (APOBEC3C, a nucleic acid editing deaminase) inherently restrict Zika virus infection. Furthermore, we demonstrate that the regulation of cellular mRNA decay and RNA splicing are compromised by Zika virus infection as well as by sfRNA alone. Collectively, these results reveal the large extent to which Zika virus-derived sfRNAs interact with cellular RNA-binding proteins and highlight the potential for widespread dysregulation of post-transcriptional control which likely limits the effective response of these cells to viral infection.

Authors+Show Affiliations

Colorado State University, United States.Colorado State University, United States.Colorado State University, United States.Colorado State University.Colorado State University, United States.Colorado State University, United States.Colorado State University, United States.Microbiology, Immunology and Pathology, Colorado State University, United States.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31519749

Citation

Michalski, Daniel, et al. "Zika Virus Noncoding sfRNAs Sequester Multiple Host-derived RNA-binding Proteins and Modulate mRNA Decay and Splicing During Infection." The Journal of Biological Chemistry, 2019.
Michalski D, Ontiveros JG, Russo J, et al. Zika virus noncoding sfRNAs sequester multiple host-derived RNA-binding proteins and modulate mRNA decay and splicing during infection. J Biol Chem. 2019.
Michalski, D., Ontiveros, J. G., Russo, J., Charley, P. A., Anderson, J. R., Heck, A. M., ... Wilusz, J. (2019). Zika virus noncoding sfRNAs sequester multiple host-derived RNA-binding proteins and modulate mRNA decay and splicing during infection. The Journal of Biological Chemistry, doi:10.1074/jbc.RA119.009129.
Michalski D, et al. Zika Virus Noncoding sfRNAs Sequester Multiple Host-derived RNA-binding Proteins and Modulate mRNA Decay and Splicing During Infection. J Biol Chem. 2019 Sep 13; PubMed PMID: 31519749.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Zika virus noncoding sfRNAs sequester multiple host-derived RNA-binding proteins and modulate mRNA decay and splicing during infection. AU - Michalski,Daniel, AU - Ontiveros,J Gustavo, AU - Russo,Joseph, AU - Charley,Phillida A, AU - Anderson,John R, AU - Heck,Adam M, AU - Geiss,Brian J, AU - Wilusz,Jeffrey, Y1 - 2019/09/13/ PY - 2019/09/13/accepted PY - 2019/04/30/received PY - 2019/9/15/entrez KW - 5'-3' exoribonuclease (XRN1) KW - RNA editing KW - RNA splicing KW - RNA turnover KW - RNA virus KW - Zika virus KW - flavivirus KW - posttranscriptional regulation KW - subgenomic flavivirus RNA (sfRNA) JF - The Journal of biological chemistry JO - J. Biol. Chem. N2 - Insect-borne flaviviruses produce a 300-500 base long noncoding RNA, termed subgenomic flavivirus RNA (sfRNA), by stalling the cellular 5'-3' exoribonuclease 1 (XRN1) via structures located in their 3' UTRs. In this study, we demonstrate that sfRNA production by Zika virus represses XRN1 analogous to what we have previously shown for other flaviviruses. Using protein-RNA reconstitution and a stringent RNA pulldown assay with human choriocarcinoma (JAR) cells, we demonstrate that the sfRNAs from both dengue type 2 and Zika viruses interact with a common set of 21 RNA-binding proteins that contribute to the regulation of post-transcriptional processes in the cell, including splicing, RNA stability and translation. We found that four of these sfRNA-interacting host proteins - DEAD-box helicase 6 (DDX6) and enhancer of mRNA decapping 3 (EDC3) (two RNA decay factors), phosphorylated adaptor for RNA export (PHAX, a regulator of the biogenesis of the splicing machinery), and apolipoprotein B mRNA-editing enzyme catalytic subunit 3C (APOBEC3C, a nucleic acid editing deaminase) inherently restrict Zika virus infection. Furthermore, we demonstrate that the regulation of cellular mRNA decay and RNA splicing are compromised by Zika virus infection as well as by sfRNA alone. Collectively, these results reveal the large extent to which Zika virus-derived sfRNAs interact with cellular RNA-binding proteins and highlight the potential for widespread dysregulation of post-transcriptional control which likely limits the effective response of these cells to viral infection. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/31519749/Zika_virus_noncoding_sfRNAs_sequester_multiple_host-derived_RNA-binding_proteins_and_modulate_mRNA_decay_and_splicing_during_infection L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=31519749 DB - PRIME DP - Unbound Medicine ER -