The loss of DHX15 impairs endothelial energy metabolism, lymphatic drainage and tumor metastasis in mice

Ribera, Jordi; Portolés, Irene; Córdoba-Jover, Bernat; Rodríguez-Vita, Juan; Casals, Gregori; Presa, Bernardino González-de la; Graupera, Mariona; Solsona-Vilarrasa, Estel; Garcı́a-Ruiz, Carmen; Fernández‐Checa, José C.; Sòria, Guadalupe; Tudela, Raúl; Esteve‐Codina, Anna; Espadas, Guadalupe; Sabidó, Eduard; Jiménez, Wladimiro; Sessa, William C.; Morales-Ruíz, Manuel

doi:10.1038/s42003-021-02722-w

Cited by 6 publications

(15 citation statements)

References 78 publications

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“…This downregulation resulted in reduced lactate production, suggesting impairment of glycolytic activity in Dhx15-depleted mosquito cells. Also in mice, Dhx15 has previously been linked to energy metabolism but in contrast to our deep-sequencing data, various glycolytic genes were transcriptionally upregulated upon Dhx15 knockdown in mouse endothelial cells (73). It is currently unclear what explains this discrepancy, but it is likely that overall differences in the metabolic state and integration of other regulatory mechanisms within the different experimental systems account for various metabolic outcomes.…”

Section: Discussioncontrasting

confidence: 87%

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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Section: Discussioncontrasting

confidence: 87%

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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show abstract

“…This downregulation resulted in reduced lactate levels, suggesting impairment of glycolytic activity in Dhx15-depleted mosquito cells. Also in mice, Dhx15 has previously been linked to energy metabolism but in contrast to our deep-sequencing data, various glycolytic genes were transcriptionally upregulated upon Dhx15 knockdown in mouse endothelial cells [73]. It is currently unclear what explains this discrepancy but it is likely that overall differences in the metabolic state and integration of other regulatory mechanisms within the two distinct experimental systems account for different metabolic outcomes.…”

Section: Dhx15 Controls Glycolysis and Arbovirus Replication In Mosqu...contrasting

confidence: 88%

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

Machado

Qu²,

Koopman³

et al. 2022

PLoS Pathog

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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 of the molecular interactions of arboviruses with their mosquito hosts is 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 Sindbis virus. Amongst these, the three DEAD-box RNA helicases AAEL004419/Dhx15, AAEL008728, and AAEL004859 also acted as antiviral factors in dengue and CHIKV infections. Here, we explored 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 and CHIKV infected cells resulted in differential expression of 856 and 372 genes, respectively. Interestingly, amongst the consistently downregulated genes, glycolytic process was the most enriched gene ontology (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 indicated that Dhx15 silencing indeed 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 glycolytic genes. Our data suggests that Dhx15 regulates replication of CHIKV, and possibly other arboviruses, by controlling glycolysis in mosquito cells.

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“…We also described a relevant function of Dhx15 in lymphatic and blood vasculature development and functioning in vertebrates. In this context, we demonstrated the role of Dhx15 as a regulator of lung metastasis in a syngeneic mouse model of metastasis [7]. Dhx15 gene deficiency resulted in significantly reduced metastasis due to lymphatic vascular defects and impaired endothelial energy metabolism.…”

Section: Introductionmentioning

confidence: 89%

“…We previously described that Dhx15 is a downstream target of Akt and that there is a regulatory crosstalk in the expression of both proteins [6,7]. DHX15 expression is not organ-specific and has an ubiquitous variable gene expression.…”

Section: Introductionmentioning

confidence: 99%

Identification of Dhx15 as a Major Regulator of Liver Development, Regeneration, and Tumor Growth in Zebrafish and Mice

Portolés,

Ribera,

Fernandez-Galán

et al. 2024

IJMS

Self Cite

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RNA helicase DHX15 plays a significant role in vasculature development and lung metastasis in vertebrates. In addition, several studies have demonstrated the overexpression of DHX15 in the context of hepatocellular carcinoma. Therefore, we hypothesized that this helicase may play a significant role in liver regeneration, physiology, and pathology. Dhx15 gene deficiency was generated by CRISPR/Cas9 in zebrafish and by TALEN-RNA in mice. AUM Antisense-Oligonucleotides were used to silence Dhx15 in wild-type mice. The hepatocellular carcinoma tumor induction model was generated by subcutaneous injection of Hepa 1-6 cells. Homozygous Dhx15 gene deficiency was lethal in zebrafish and mouse embryos. Dhx15 gene deficiency impaired liver organogenesis in zebrafish embryos and liver regeneration after partial hepatectomy in mice. Also, heterozygous mice presented decreased number and size of liver metastasis after Hepa 1-6 cells injection compared to wild-type mice. Dhx15 gene silencing with AUM Antisense-Oligonucleotides in wild-type mice resulted in 80% reduced expression in the liver and a significant reduction in other major organs. In addition, Dhx15 gene silencing significantly hindered primary tumor growth in the hepatocellular carcinoma experimental model. Regarding the potential use of DHX15 as a diagnostic marker for liver disease, patients with hepatocellular carcinoma showed increased levels of DHX15 in blood samples compared with subjects without hepatic affectation. In conclusion, Dhx15 is a key regulator of liver physiology and organogenesis, is increased in the blood of cirrhotic and hepatocellular carcinoma patients, and plays a key role in controlling hepatocellular carcinoma tumor growth and expansion in experimental models.

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The loss of DHX15 impairs endothelial energy metabolism, lymphatic drainage and tumor metastasis in mice

Cited by 6 publications

References 78 publications

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

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

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

Identification of Dhx15 as a Major Regulator of Liver Development, Regeneration, and Tumor Growth in Zebrafish and Mice

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