Untangling the roles of RNA helicases in antiviral innate immunity

Baldaccini, Morgane; Pfeffer, Sébastien

doi:10.1371/journal.ppat.1010072

Cited by 22 publications

(20 citation statements)

References 132 publications

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“…Tertiary structure of human Dicer shows a L-shape arrangement that forms a pocket to accommodate the pre-miRNA (Figure 3a,b). The basal segment of the protein is composed by two helicase-like domains, very similar to those observed in the family of ATP-dependent DExD/H-box helicases [52]. The function of the helicase-like domain in human Dicer is not totally understood since the human protein does not depend on ATP for its catalytic activity [46].…”

Section: Cytoplasmic Processors: Dicermentioning

confidence: 77%

A Structural View of miRNA Biogenesis and Function

Leitão

Enguita

2022

ncRNA

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Micro-RNAs (miRNAs) are a class of non-coding RNAs (ncRNAs) that act as post-transcriptional regulators of gene expression. Since their discovery in 1993, they have been the subject of deep study due to their involvement in many important biological processes. Compared with other ncRNAs, miRNAs are generated from devoted transcriptional units which are processed by a specific set of endonucleases. The contribution of structural biology methods for understanding miRNA biogenesis and function has been essential for the dissection of their roles in cell biology and human disease. In this review, we summarize the application of structural biology for the characterization of the molecular players involved in miRNA biogenesis (processors and effectors), starting from the X-ray crystallography methods to the more recent cryo-electron microscopy protocols.

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Section: Cytoplasmic Processors: Dicermentioning

confidence: 77%

A Structural View of miRNA Biogenesis and Function

Leitão

Enguita

2022

ncRNA

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“…DEAD-box helicases are a large family of conserved RNA-binding proteins that belong to the broader group of cellular DExD/H helicases, with emerging evidence that it plays a role in the recognition of foreign nucleic acids and the modulation of viral infection ( Taschuk & Cherry, 2020 ). DEAD-box helicases can play an essential role in sensing viral infection and directly affecting virus RNA by participating in the RNAi pathway and Toll-like and retinoic acid-inducible gene-I-like receptors signaling pathway, for example ( Ahmad & Hur, 2015 ; Baldaccini & Pfeffer, 2021 ; Su et al., 2022 ). However, there is evidence that noncoding subgenomic flavivirus RNA from ZIKV can bind to DEAD/H-box helicase ME31B in Ae.…”

Section: Resultsmentioning

confidence: 99%

Interspecies Isobaric Labeling-Based Quantitative Proteomics Reveals Protein Changes in the Ovary of Aedes aegypti Coinfected With ZIKV and Wolbachia

Ramos

Martins²,

Murillo³

et al. 2022

Front. Cell. Infect. Microbiol.

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Zika is a vector-borne disease caused by an arbovirus (ZIKV) and overwhelmingly transmitted by Ae. aegypti. This disease is linked to adverse fetal outcomes, mostly microcephaly in newborns, and other clinical aspects such as acute febrile illness and neurologic complications, for example, Guillain-Barré syndrome. One of the most promising strategies to mitigate arbovirus transmission involves releasing Ae. aegypti mosquitoes carrying the maternally inherited endosymbiont bacteria Wolbachia pipientis. The presence of Wolbachia is associated with a reduced susceptibility to arboviruses and a fitness cost in mosquito life-history traits such as fecundity and fertility. However, the mechanisms by which Wolbachia influences metabolic pathways leading to differences in egg production remains poorly known. To investigate the impact of coinfections on the reproductive tract of the mosquito, we applied an isobaric labeling-based quantitative proteomic strategy to investigate the influence of Wolbachia wMel and ZIKV infection in Ae. aegypti ovaries. To the best of our knowledge, this is the most complete proteome of Ae. aegypti ovaries reported so far, with a total of 3913 proteins identified, were also able to quantify 1044 Wolbachia proteins in complex sample tissue of Ae. aegypti ovary. Furthermore, from a total of 480 mosquito proteins modulated in our study, we discuss proteins and pathways altered in Ae. aegypti during ZIKV infections, Wolbachia infections, coinfection Wolbachia/ZIKV, and compared with no infection, focusing on immune and reproductive aspects of Ae. aegypti. The modified aspects mainly were related to the immune priming enhancement by Wolbachia presence and the modulation of the Juvenile Hormone pathway caused by both microorganism’s infection.

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“…DEAD box helicases have a large array of functions in general RNA metabolism as well as controlling antiviral immunity (63–65). Prime examples are the DEAD-box helicases Dicer-2 and the RIG-I like RNA helicases, which are essential for sensing viral RNA in invertebrates and vertebrates, respectively (24, 29).…”

Section: Discussionmentioning

confidence: 99%

The DEAD-box RNA helicase Dhx15 controls glycolysis and arbovirus replication in Aedes aegypti mosquito cells

Miesen

Machado

et al. 2022

Preprint

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Aedes aegypti mosquitoes are responsible for the transmission of arthropod-borne (arbo)viruses including dengue and chikungunya virus (CHIKV), but in contrast to human hosts, arbovirus infected mosquitoes are able to efficiently control virus replication to sub-pathological levels. Yet, our knowledge about the molecular interactions of arboviruses with their mosquito hosts is largely incomplete. Here, we aimed to identify and characterize novel host genes that control arbovirus replication in Aedes mosquitoes. RNA binding proteins (RBPs) are well known to regulate immune signaling pathways in all kingdoms of life. We therefore performed a knockdown screen targeting 461 genes encoding predicted RBPs in Aedes aegypti Aag2 cells and identified 15 genes with antiviral activity against a Sindbis reporter virus. Amongst these, three DEAD-box RNA helicases, AAEL004419/Dhx15, AAEL008728 and AAEL004859 also acted as antiviral factors in dengue and CHIKV infections. Here, we explore the mechanism of Dhx15 in regulating an antiviral transcriptional response in mosquitoes by silencing Dhx15 in Aag2 cells followed by deep-sequencing of poly-A enriched RNAs. Dhx15 knockdown in uninfected or CHIKV-infected cells resulted in differential expression of 856 and 372 genes, respectively. Interestingly, amongst the consistently downregulated genes, glycolytic process was the most strongly enriched GO term as the expression of all core enzymes of the glycolytic pathway was reduced, suggesting that Dhx15 regulates glycolytic function. A decrease in lactate production supported the observation that Dhx15 silencing functionally impaired glycolysis. Modified rates of glycolytic metabolism have been implicated in controlling the replication of several classes of viruses and strikingly, infection of Aag2 cells with CHIKV by itself also resulted in the decrease of several glycolysis genes. Our data suggests that Dhx15 regulates replication of CHIKV, and possibly other arboviruses, by controlling glycolysis in mosquito cells.

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Untangling the roles of RNA helicases in antiviral innate immunity

Cited by 22 publications

References 132 publications

A Structural View of miRNA Biogenesis and Function

A Structural View of miRNA Biogenesis and Function

Interspecies Isobaric Labeling-Based Quantitative Proteomics Reveals Protein Changes in the Ovary of Aedes aegypti Coinfected With ZIKV and Wolbachia

The DEAD-box RNA helicase Dhx15 controls glycolysis and arbovirus replication in Aedes aegypti mosquito cells

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