Back to Search
Start Over
Widespread remodeling of the m 6 A RNA-modification landscape by a viral regulator of RNA processing and export.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Jul 27; Vol. 118 (30). - Publication Year :
- 2021
-
Abstract
- N <superscript>6</superscript> -methyladenosine (m <superscript>6</superscript> A) is the most abundant internal messenger RNA (mRNA) modification, contributing to the processing, stability, and function of methylated RNAs. Methylation occurs in the nucleus during pre-mRNA synthesis and requires a core methyltransferase complex consisting of METTL3, METTL14, and WTAP. During herpes simplex virus (HSV-1) infection, cellular gene expression is profoundly suppressed, allowing the virus to monopolize the host transcription and translation apparatus and antagonize antiviral responses. The extent to which HSV-1 uses or manipulates the m <superscript>6</superscript> A pathway is not known. Here, we show that, in primary fibroblasts, HSV-1 orchestrates a striking redistribution of the nuclear m <superscript>6</superscript> A machinery that progresses through the infection cycle. METTL3 and METTL14 are dispersed into the cytoplasm, whereas WTAP remains nuclear. Other regulatory subunits of the methyltransferase complex, along with the nuclear m <superscript>6</superscript> A-modified RNA binding protein YTHDC1 and nuclear demethylase ALKBH5, are similarly redistributed. These changes require ICP27, a viral regulator of host mRNA processing that mediates the nucleocytoplasmic export of viral late mRNAs. Viral gene expression is initially reduced by small interfering RNA (siRNA)-mediated inactivation of the m <superscript>6</superscript> A methyltransferase but becomes less impacted as the infection advances. Redistribution of the nuclear m <superscript>6</superscript> A machinery is accompanied by a wide-scale reduction in the installation of m <superscript>6</superscript> A and other RNA modifications on both host and viral mRNAs. These results reveal a far-reaching mechanism by which HSV-1 subverts host gene expression to favor viral replication.<br />Competing Interests: The authors declare no competing interest.
- Subjects :
- Animals
Cell Cycle Proteins
Cell Line
Chlorocebus aethiops
Gene Expression Regulation, Enzymologic
Humans
Methyltransferases genetics
RNA Interference
RNA Processing, Post-Transcriptional
RNA Splicing Factors
RNA, Messenger genetics
RNA-Seq methods
Vero Cells
Herpesvirus 1, Human physiology
Methyltransferases metabolism
RNA, Messenger metabolism
Virus Replication physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 118
- Issue :
- 30
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 34282019
- Full Text :
- https://doi.org/10.1073/pnas.2104805118