DDX5/METTL3-METTL14/YTHDF2 Axis Regulates Replication of Influenza A Virus

Zhao, Lingcai; Zhao, Yongzhen; Liu, Qingzheng; Huang, Jingjin; Lu, Yuanlu; Ping, Jihui

doi:10.1128/spectrum.01098-22

Cited by 15 publications

(9 citation statements)

References 58 publications

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“…Previous study has reported that METTL3 impedes the degradation of IRAKM, a key negative regulator of TLR4, consequently leading to the suppression of TLR4 and its associated downstream signaling pathways [ 47 ]. METTL14 collaborates with METTL3 in regulating the replication of various viruses, including HCV [ 48 ], HDV [ 49 ], IAV [ 50 ], HSV-1 [ 51 ] and HIV [ 52 ], suggesting a supporting role for METTL14 in these viral infections. However, in the case of viruses like PCV2 [ 53 ], PRV [ 54 ], VSV [ 55 ], and EBV [ 24 ], METTL14 is shown to play a crucial role in promoting their replication.…”

Section: Discussionmentioning

confidence: 99%

Classical swine fever virus non-structural protein 5B hijacks host METTL14-mediated m6A modification to counteract host antiviral immune response

Chen,

Song,

et al. 2024

PLoS Pathog

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Classical Swine Fever (CSF), caused by the Classical Swine Fever Virus (CSFV), inflicts significant economic losses on the global pig industry. A key factor in the challenge of eradicating this virus is its ability to evade the host’s innate immune response, leading to persistent infections. In our study, we elucidate the molecular mechanism through which CSFV exploits m6A modifications to circumvent host immune surveillance, thus facilitating its proliferation. We initially discovered that m6A modifications were elevated both in vivo and in vitro upon CSFV infection, particularly noting an increase in the expression of the methyltransferase METTL14. CSFV non-structural protein 5B was found to hijack HRD1, the E3 ubiquitin ligase for METTL14, preventing METTL14 degradation. MeRIP-seq analysis further revealed that METTL14 specifically targeted and methylated TLRs, notably TLR4. METTL14-mediated regulation of TLR4 degradation, facilitated by YTHDF2, led to the accelerated mRNA decay of TLR4. Consequently, TLR4-mediated NF-κB signaling, a crucial component of the innate immune response, is suppressed by CSFV. Collectively, these data effectively highlight the viral evasion tactics, shedding light on potential antiviral strategies targeting METTL14 to curb CSFV infection.

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Section: Discussionmentioning

confidence: 99%

Classical swine fever virus non-structural protein 5B hijacks host METTL14-mediated m6A modification to counteract host antiviral immune response

Chen,

Song,

et al. 2024

PLoS Pathog

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“…Previous studies have demonstrated that the DDX5 protein is a multifunctional DEAD-box RNA helicase and a transcription cofactor that participates in a variety of cellular activities across species ( Nyamao et al, 2019 ). Previous studies have additionally demonstrated that DDX5 is involved in a variety of clinical diseases ( Ariumi, 2022 ; Zhang et al, 2022 ; Zhao et al, 2022 ), especially carcinogenesis and the development of cancer ( Zheng et al, 2021 ; Le et al, 2022 ). The common molecular pathways involved in the function of DDX5 in carcinogenesis remain to be thoroughly investigated.…”

Section: Discussionmentioning

confidence: 99%

Pan-cancer analysis of the prognostic and immunological roles of DEAD-box helicase 5 (DDX5) in human tumors

Liu

Zhang

et al. 2022

Front. Genet.

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Background: Recent studies have demonstrated the significance of the DEAD-box helicase 5 (DDX5) gene, which is involved in pathways concerning the modification of RNA structures. DDX5 functions as a coregulator of cellular transcription and splicing, and participates in the processing of small noncoding RNAs. The aberrant regulation of DDX5 expression possibly plays a significant role in the genesis of cancer. However, there are no comprehensive pan-cancer studies on DDX5. This study is the first to conduct a pan-cancer analysis of DDX5 for aiding the diagnosis and treatment of cancer.Methods: The gene expression, genetic alterations, protein phosphorylation, promoter methylation, immune infiltration, and enrichment analyses of DDX5 were performed using data retrieved from The Cancer Genome Atlas (TCGA), Genotype-tissue Expression (GTEx), Human Protein Atlas (HPA), Tumor Immunological Estimation Resource 2.0 (TIMER2.0), Gene Expression Profiling Interactive Analysis (GEPIA), DNA methylation interactive visualization database (DNMIVD), and Search Tool for the Retrieval of Interaction Genes/Proteins (STRING). Data analyses were performed with the R software and other webtools.Results: The expression of DDX5 mRNA decreased significantly in 17 cancer types, but increased significantly in eight cancer types. The enhanced expression of DDX5 mRNA in the tumor samples was related to decreased overall survival (OS), progression-free interval (PFI), and disease-specific survival (DSS) in three cancers, but increased OS, PFI, and DSS in other cancers. The DNA promoter methylation level was significantly reduced in eight cancer types, and there were exceptions in the methylation levels of the DDX5 promoter in four cancer types. The expression of DDX5 mRNA was highly correlated with the infiltration of CD8+ T cells, cancer-associated fibroblasts, and B cells in a wide variety of malignancies. The findings revealed a strong association between DDX5 and its co-expressed genes in numerous cancer types. Enrichment analysis suggested that DDX5 was associated with multiple cellular pathways, including RNA splicing, Notch signaling pathway, and viral carcinogenesis, which was consistent with the results of previous studies.Conclusion: The findings obtained herein provide further information on the oncogenic potential of DDX5 in diverse tumor types. We propose that DDX5 has important roles in tumor immunity and the diagnosis of cancer.

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“…Targeting m6A not only mediates the control of the innate immune response but also blocks the replication of several viruses, including SARS-CoV-2 and influenza A virus ( 149 , 150 ). The cytosolic m6A-binding proteins YTHDF1, YTHDF2, and YTHDF3 undergo phase separation ( 151 – 155 ); however, the association between the LLPS and the function of YTHDF proteins remains to be confirmed.…”

Section: Roles Of Llps Condensation During Innate Antiviral Immunitymentioning

confidence: 99%

Molecular mechanisms and cellular functions of liquid-liquid phase separation during antiviral immune responses

Yang

Shen

et al. 2023

Front. Immunol.

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Spatiotemporal separation of cellular components is vital to ensure biochemical processes. Membrane-bound organelles such as mitochondria and nuclei play a major role in isolating intracellular components, while membraneless organelles (MLOs) are accumulatively uncovered via liquid-liquid phase separation (LLPS) to mediate cellular spatiotemporal organization. MLOs orchestrate various key cellular processes, including protein localization, supramolecular assembly, gene expression, and signal transduction. During viral infection, LLPS not only participates in viral replication but also contributes to host antiviral immune responses. Therefore, a more comprehensive understanding of the roles of LLPS in virus infection may open up new avenues for treating viral infectious diseases. In this review, we focus on the antiviral defense mechanisms of LLPS in innate immunity and discuss the involvement of LLPS during viral replication and immune evasion escape, as well as the strategy of targeting LLPS to treat viral infectious diseases.

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DDX5/METTL3-METTL14/YTHDF2 Axis Regulates Replication of Influenza A Virus

Abstract: The replication and transcription of influenza virus depends on the participation of many host factors in cells. Exploring the relationship between viruses and host factors will help us fully understand the characteristics and pathogenic mechanisms of influenza viruses.

Cited by 15 publications

References 58 publications

Classical swine fever virus non-structural protein 5B hijacks host METTL14-mediated m6A modification to counteract host antiviral immune response

Classical swine fever virus non-structural protein 5B hijacks host METTL14-mediated m6A modification to counteract host antiviral immune response

Pan-cancer analysis of the prognostic and immunological roles of DEAD-box helicase 5 (DDX5) in human tumors

Molecular mechanisms and cellular functions of liquid-liquid phase separation during antiviral immune responses

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