YAP Transcriptional Activity Dictates Cell Response to TNF In Vitro

Caire, Robin; Dalix, Elisa; Chafchafi, Marwa; Thomas, Mireille; Linossier, Marie‐Thérèse; Normand, Marie-Thérèse Le; Guignandon, Alain; Vico, Laurence; Marotte, Hubert

doi:10.3389/fimmu.2022.856247

Cited by 15 publications

(9 citation statements)

References 53 publications

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“…YAP/TAZ are known to control the expression of actin-related tension proteins MLC2 and DIAPH1, which are important for autophagosome formation 14 . However, we did not evaluate these genes in this work given that we recently showed that MLC2 expression was not detected in HEK293 cells and DIAPH1 expression was similar in HEK293 WT and YAP −/− cells 41 . To confirm the findings of the transcriptional analysis, we monitored autophagic flux in WT, YAP −/− , and YAPΔTEAD −/+ cells.…”

Section: Resultsmentioning

confidence: 99%

YAP promotes cell-autonomous immune responses to tackle intracellular Staphylococcus aureus in vitro

et al. 2022

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Transcriptional cofactors YAP/TAZ have recently been found to support autophagy and inflammation, which are part of cell-autonomous immunity and are critical in antibacterial defense. Here, we studied the role of YAP against Staphylococcus aureus using CRISPR/Cas9-mutated HEK293 cells and a primary cell-based organoid model. We found that S. aureus infection increases YAP transcriptional activity, which is required to reduce intracellular S. aureus replication. A 770-gene targeted transcriptomic analysis revealed that YAP upregulates genes involved in autophagy/lysosome and inflammation pathways in both infected and uninfected conditions. The YAP-TEAD transcriptional activity promotes autophagic flux and lysosomal acidification, which are then important for defense against intracellular S. aureus. Furthermore, the staphylococcal toxin C3 exoenzyme EDIN-B was found effective in preventing YAP-mediated cell-autonomous immune response. This study provides key insights on the anti-S. aureus activity of YAP, which could be conserved for defense against other intracellular bacteria.

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Section: Resultsmentioning

confidence: 99%

YAP promotes cell-autonomous immune responses to tackle intracellular Staphylococcus aureus in vitro

et al. 2022

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“…Crosstalk between innate immune pathways and the Hippo-YAP pathway have been documented previously. The release of inflammatory cytokines, including TNFα, IL-6, and most notably, the inflammasome-generated cytokine IL-1β ( Taniguchi et al, 2015 ; Liu et al, 2020 ; Wang et al, 2020 ; Caire et al, 2022 ), have been shown to stabilize levels of YAP protein and activate its target transcriptional pathways. The effects of activated YAP appear to be cell-type specific.…”

Section: Discussionmentioning

confidence: 99%

“…In tubular epithelial cells, this pathway typically results in cell proliferation and contributes to regeneration of epithelial cells after injury ( Taniguchi et al, 2015 ; Xu et al, 2016 ; Chen et al, 2018 ). Activation of YAP in mononuclear immune cells by inflammatory cytokines appears to promote inflammatory pathways further, including the upregulation of inflammatory cytokines/chemokines ( Liu et al, 2020 ; Caire et al, 2022 ). While it seems likely that the reduced renal levels of YAP and YAP target genes, including Myc, that we show here in female RC/RC: Casp1 KO mice contribute to their suppressed cystic disease, the specific contribution of this pathway to direct effects on tubule cell proliferation or to the inflammatory environment influencing cyst growth has not yet been studied.…”

Section: Discussionmentioning

confidence: 99%

Caspase-1 and the inflammasome promote polycystic kidney disease progression

Swenson-Fields

Ward

Lopez

et al. 2022

Front. Mol. Biosci.

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We and others have previously shown that the presence of renal innate immune cells can promote polycystic kidney disease (PKD) progression. In this study, we examined the influence of the inflammasome, a key part of the innate immune system, on PKD. The inflammasome is a system of molecular sensors, receptors, and scaffolds that responds to stimuli like cellular damage or microbes by activating Caspase-1, and generating critical mediators of the inflammatory milieu, including IL-1β and IL-18. We provide evidence that the inflammasome is primed in PKD, as multiple inflammasome sensors were upregulated in cystic kidneys from human ADPKD patients, as well as in kidneys from both orthologous (PKD1RC/RC or RC/RC) and non-orthologous (jck) mouse models of PKD. Further, we demonstrate that the inflammasome is activated in female RC/RC mice kidneys, and this activation occurs in renal leukocytes, primarily in CD11c+ cells. Knock-out of Casp1, the gene encoding Caspase-1, in the RC/RC mice significantly restrained cystic disease progression in female mice, implying sex-specific differences in the renal immune environment. RNAseq analysis implicated the promotion of MYC/YAP pathways as a mechanism underlying the pro-cystic effects of the Caspase-1/inflammasome in females. Finally, treatment of RC/RC mice with hydroxychloroquine, a widely used immunomodulatory drug that has been shown to inhibit the inflammasome, protected renal function specifically in females and restrained cyst enlargement in both male and female RC/RC mice. Collectively, these results provide evidence for the first time that the activated Caspase-1/inflammasome promotes cyst expansion and disease progression in PKD, particularly in females. Moreover, the data suggest that this innate immune pathway may be a relevant target for therapy in PKD.

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“…In this study, phosphorylation of YAP was decreased by the novel ROCK inhibitors. YAP, a member of Hippo signaling pathway, is involved in senescence and regulates proliferation and EMT through TGF-β signaling [ 31 , 32 ]. ROCK drives TEAD/YAP transcription and regulates intracellular tension [ 33 , 34 ].…”

Section: Discussionmentioning

confidence: 99%

Novel ROCK Inhibitors, Sovesudil and PHP-0961, Enhance Proliferation, Adhesion and Migration of Corneal Endothelial Cells

Kim

Shin

Lee³

2022

IJMS

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The loss or dysfunction of human corneal endothelial cells (hCEnCs) is a leading cause of blindness due to corneal failure. Corneal transplantation with a healthy donor cornea has been the only available treatment for corneal endothelial disease. However, the need for way to regenerate the CEnCs has been increased due to the global shortage of donor corneas. The aim of the study is to investigate whether novel Rho-kinase (ROCK) inhibitors can induce the cultivation and regeneration of hCEnCs. Cultured hCEnCs were treated with Y-27632, sovesudil, or PHP-0961 for 24 h. Cellular responses, including cell viability, cytotoxicity, proliferation, and Ki67 expression with ROCK inhibitors were evaluated. We also evaluated wound healing and cell adhesion assays. Porcine corneas were used ex vivo to evaluate the effects of Y-27632, sovesudil, and PHP-0961 on wound healing and regeneration. We performed live/dead cell assays and immunofluorescence staining for SRY (sex determining region Y)-box 2 (SOX2), β-catenin, and ZO-1 on porcine corneas after ROCK inhibitor treatments. Cell viability, cell proliferation rate, and the number of Ki67-positive cells were higher in Y-27632, sovesudil and PHP-0961 treated cells compared to the control. There was no difference in LDH cytotoxicity test between any groups. Cells treated with Y-27632, sovesudil and PHP-0961 showed faster migration, wound healing, and cell adhesion. In the porcine ex vivo experiments, wound healing, the number of live cells, and SOX2-positive cells were higher in Y-27632, sovesudil and PHP-0961 treated corneas. In all experiments, sovesudil and PHP-0961, the novel ROCK inhibitors, were equal or superior to the results of the ROCK inhibitor positive control, Y-27632. In conclusion, sovesudil and PHP-0961, novel ROCK inhibitors have the capacity to regenerate hCEnCs by enhancing cell proliferation and adhesion between cells.

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YAP Transcriptional Activity Dictates Cell Response to TNF In Vitro

Cited by 15 publications

References 53 publications

YAP promotes cell-autonomous immune responses to tackle intracellular Staphylococcus aureus in vitro

YAP promotes cell-autonomous immune responses to tackle intracellular Staphylococcus aureus in vitro

Caspase-1 and the inflammasome promote polycystic kidney disease progression

Novel ROCK Inhibitors, Sovesudil and PHP-0961, Enhance Proliferation, Adhesion and Migration of Corneal Endothelial Cells

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