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Published on: March 5, 2022
Altered m6A Modification of Specific Cellular Transcripts Affects Flaviviridae Infection
Nandan S Gokhale1, Alexa B R McIntyre2, Melissa D Mattocks3
1Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27705, USA.
Abstract:
The RNA modification N6-methyladenosine (m6A) modulates mRNA fate and thus affects many biological processes. We analyzed m6A across the transcriptome following infection by dengue virus (DENV), Zika virus (ZIKV), West Nile virus (WNV), and hepatitis C virus (HCV). We found that infection by these viruses in the Flaviviridae family alters m6A modification of specific cellular transcripts, including RIOK3 and CIRBP. During viral infection, the addition of m6A to RIOK3 promotes its translation, while loss of m6A in CIRBP promotes alternative splicing. Importantly, viral activation of innate immune sensing or the endoplasmic reticulum (ER) stress response contributes to the changes in m6A in RIOK3 or CIRBP, respectively. Further, several transcripts with infection-altered m6A profiles, including RIOK3 and CIRBP, encode proteins that influence DENV, ZIKV, and HCV infection. Overall, this work reveals that cellular signaling pathways activated during viral infection lead to alterations in m6A modification of host mRNAs to regulate infection.
Insights
Viral infections alter cellular RNA modifications, specifically N⁶-methyladenosine (m⁶A), impacting host gene expression. This study reveals how m⁶A changes in RIOK3 and CIRBP regulate Flaviviridae family virus infections.
Area of Science:
- Molecular Biology
- Virology
- Epigenetics
Background:
- N⁶-methyladenosine (m⁶A) is a prevalent mRNA modification influencing gene expression and cellular processes.
- Flaviviridae family viruses (DENV, ZIKV, WNV, HCV) are significant human pathogens.
- Understanding host-pathogen interactions at the molecular level is crucial for developing antiviral strategies.
Purpose of the Study:
- To investigate the impact of viral infection on m⁶A modification patterns across the host transcriptome.
- To identify specific cellular transcripts whose m⁶A levels are altered during infection.
- To elucidate the functional consequences of these m⁶A changes on viral replication and host response.
Main Methods:
- Transcriptome-wide analysis of m⁶A modification in cells infected with DENV, ZIKV, WNV, and HCV.
- Quantitative analysis of m⁶A levels in specific host transcripts, including RIOK3 and CIRBP.
- Assessment of the functional roles of m⁶A modifications in RIOK3 translation and CIRBP splicing during infection.
- Investigation of the link between viral-induced signaling pathways (innate immunity, ER stress) and m⁶A alterations.
Main Results:
- Viral infection by DENV, ZIKV, WNV, and HCV alters m⁶A modification of specific host transcripts, notably RIOK3 and CIRBP.
- m⁶A addition to RIOK3 enhances its translation, while m⁶A loss in CIRBP promotes alternative splicing.
- Innate immune sensing and ER stress responses activated during infection contribute to altered m⁶A levels in RIOK3 and CIRBP, respectively.
- Host proteins encoded by infection-altered m⁶A transcripts, including RIOK3 and CIRBP, influence viral replication.
Conclusions:
- Cellular signaling pathways activated during viral infection induce changes in host mRNA m⁶A modification.
- These m⁶A alterations play a regulatory role in modulating viral infection outcomes.
- Targeting m⁶A modification pathways could represent a novel therapeutic strategy against Flaviviridae infections.
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