title: Dynamics of Human and Viral RNA Methylation during Zika Virus Infection.
abstract: Infection with the flavivirus Zika (ZIKV) causes neurological, immunological, and developmental defects through incompletely understood mechanisms. We report that ZIKV infection affects viral and human RNAs by altering the topology and function of N6-adenosine methylation (m6A), a modification affecting RNA structure and function. m6A nucleosides are abundant in ZIKV RNA, with twelve m6A peaks identified across full-length ZIKV RNA. m6A in ZIKV RNA is controlled by host methyltransferases METTL3 and METTL14 and demethylases ALKBH5 and FTO, and knockdown of methyltransferases increases, while silencing demethylases decreases, ZIKV production. YTHDF family proteins, which regulate the stability of m6A-modified RNA, bind to ZIKV RNA, and their silencing increases ZIKV replication. Profiling of the m6A methylome of host mRNAs reveals that ZIKV infection alters m6A location in mRNAs, methylation motifs, and target genes modified by methyltransferases. Our results identify a mechanism by which ZIKV interacts with and alters host cell functions.
authors: Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA; Program for RNA Biology and Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Gianluigi
authors: G
authors: Lichinchi
authors: Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA.
authors: Boxuan Simen
authors: BS
authors: Zhao
authors: Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA; Program for RNA Biology and Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Yinga
authors: Y
authors: Wu
authors: Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA.
authors: Zhike
authors: Z
authors: Lu
authors: Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Yue
authors: Y
authors: Qin
authors: Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA.
authors: Chuan
authors: C
authors: He
authors: Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA; Program for RNA Biology and Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: trana@ucsd.edu.
authors: Tariq M
authors: TM
authors: Rana
mesh_terms: D000071502:AlkB Homolog 5, RNA Demethylase / Q000378:metabolism; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO / Q000378:metabolism; D002460:Cell Line; D054884:Host-Pathogen Interactions; D006801:Humans; D008745:Methylation; D008780:Methyltransferases / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D012367:RNA, Viral / Q000378:metabolism*; D014779:Virus Replication; D000071244:Zika Virus / Q000502:physiology*
chemical_list: D012367:RNA, Viral; C559920:ALKBH5 protein, human; D000071502:AlkB Homolog 5, RNA Demethylase; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human; C587355:METTL14 protein, human; D008780:Methyltransferases; C468275:METTL3 protein, human
keywords: 2′-O methylation; Zika virus; m(6)A methylation; methyltransferases