The RNA helicase DDX5 promotes viral infection via regulating N6-methyladenosine levels on the DHX58 and NFκB transcripts to dampen antiviral innate immunity

Multi-functional DEAD-box helicase 5 (DDX5), which is important in transcriptional regulation, is hijacked by diverse viruses to facilitate viral replication. However, its regulatory effect in antiviral innate immunity remains unclear. We found that DDX5 interacts with the N6-methyladenosine (m6A) w...

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Bibliographic Details
Published in:PLoS pathogens 2021-04, Vol.17 (4), p.e1009530-e1009530
Main Authors: Xu, Jian, Cai, Yunhong, Ma, ZhenBang, Jiang, Bo, Liu, Wenxiao, Cheng, Jing, Guo, Nannan, Wang, Zishu, Sealy, Joshua E, Song, Cuiping, Wang, Xiaojia, Li, Yongqing
Format: Article
Language:English
Subjects:
Acids
Biology and life sciences
Cytokines
Cytoplasm
DNA helicase
Embryo fibroblasts
Embryos
Fibroblasts
Gene expression
Immunity
Infections
Innate immunity
Kinases
Leucine
Localization
Medicine and Health Sciences
Metabolism
NF-κB protein
Nucleic acids
Nucleotides
Physical Sciences
Proteins
Receptors
Research and Analysis Methods
Retinoic acid
Ribonucleic acid
RNA
RNA helicase
RNA transport
Splicing
Stomatitis
Toll-like receptors
Transcription
Viral infections
Viruses
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Summary:Multi-functional DEAD-box helicase 5 (DDX5), which is important in transcriptional regulation, is hijacked by diverse viruses to facilitate viral replication. However, its regulatory effect in antiviral innate immunity remains unclear. We found that DDX5 interacts with the N6-methyladenosine (m6A) writer METTL3 to regulate methylation of mRNA through affecting the m6A writer METTL3-METTL14 heterodimer complex. Meanwhile, DDX5 promoted the m6A modification and nuclear export of transcripts DHX58, p65, and IKKγ by binding conserved UGCUGCAG element in innate response after viral infection. Stable IKKγ and p65 transcripts underwent YTHDF2-dependent mRNA decay, whereas DHX58 translation was promoted, resulting in inhibited antiviral innate response by DDX5 via blocking the p65 pathway and activating the DHX58-TBK1 pathway after infection with RNA virus. Furthermore, we found that DDX5 suppresses antiviral innate immunity in vivo. Our findings reveal that DDX5 serves as a negative regulator of innate immunity by promoting RNA methylation of antiviral transcripts and consequently facilitating viral propagation.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1009530