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Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) mediate cell density-dependent proinflammatory responses.

ABSTRACT: A proper inflammatory response is critical to the restoration of tissue homeostasis after injury or infection, but how such a response is modulated by the physical properties of the cellular and tissue microenvironments is not fully understood. Here, using H358, HeLa, and HEK293T cells, we report that cell density can modulate inflammatory responses through the Hippo signaling pathway. We found that NF-?? activation through the proinflammatory cytokines interleukin-1? (IL-1?) and tumor necrosis factor ? (TNF?) is not affected by cell density. However, we also noted that specific NF-?? target genes, such as cyclooxygenase 2 (COX-2), are induced much less at low cell densities than at high cell densities. Mechanistically, we observed that the transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are localized to the nucleus, bind to TEA domain transcription factors (TEADs), recruit histone deacetylase 7 (HDAC7) to the promoter region of COX-2, and repress its transcription at low cell density and that high cell density abrogates this YAP/TAZ-mediated transcriptional repression. Of note, IL-1? stimulation promoted cell migration and invasion mainly through COX-2 induction, but YAP inhibited this induction and thus cell migration and invasion. These results suggest that YAP/TAZ-TEAD interactions can repress COX-2 transcription and thereby mediate cell density-dependent modulation of proinflammatory responses. Our findings highlight that the cellular microenvironment significantly influences inflammatory responses via the Hippo pathway.

SUBMITTER: Zhang Q

PROVIDER: S-EPMC6254335 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) mediate cell density-dependent proinflammatory responses.

Zhang Qiong Q Han Xu X Chen Jinfeng J Xie Xiaomei X Xu Jiafeng J Zhao Yang Y Shen Jie J Hu Lin L Xu Pinglong P Song Hai H Zhang Long L Zhao Bin B Wang Ying-Jie YJ Xia Zongping Z

The Journal of biological chemistry 20181012 47

A proper inflammatory response is critical to the restoration of tissue homeostasis after injury or infection, but how such a response is modulated by the physical properties of the cellular and tissue microenvironments is not fully understood. Here, using H358, HeLa, and HEK293T cells, we report that cell density can modulate inflammatory responses through the Hippo signaling pathway. We found that NF-κΒ activation through the proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis ...[more]

PMID: 30315101

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Project description:Background and aimsActivated hepatocytes are hypothesized to be a major source of signals that drive cirrhosis, but the biochemical pathways that convert hepatocytes into such a state are unclear. We examined the role of the Hippo pathway transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in hepatocytes to facilitate cell-cell interactions that stimulate liver inflammation and fibrosis.Approach and resultsUsing a variety of genetic, metabolic, and liver injury models in mice, we manipulated Hippo signaling in hepatocytes and examined its effects in nonparenchymal cells to promote liver inflammation and fibrosis. YAP-expressing hepatocytes rapidly and potently activate the expression of proteins that promote fibrosis (collagen type I alpha 1 chain, tissue inhibitor of metalloproteinase 1, platelet-derived growth factor c, transforming growth factor β2) and inflammation (tumor necrosis factor, interleukin 1β). They stimulate expansion of myofibroblasts and immune cells, followed by aggressive liver fibrosis. In contrast, hepatocyte-specific YAP and YAP/TAZ knockouts exhibit limited myofibroblast expansion, less inflammation, and decreased fibrosis after CCl4 injury despite a similar degree of necrosis as controls. We identified cellular communication network factor 1 (CYR61) as a chemokine that is up-regulated by hepatocytes during liver injury but is expressed at significantly lower levels in mice with hepatocyte-specific deletion of YAP or TAZ. Gain-of-function and loss-of-function experiments with CYR61 in vivo point to it being a key chemokine controlling liver fibrosis and inflammation in the context of YAP/TAZ. There is a direct correlation between levels of YAP/TAZ and CYR61 in liver tissues of patients with high-grade nonalcoholic steatohepatitis.ConclusionsLiver injury in mice and humans increases levels of YAP/TAZ/CYR61 in hepatocytes, thus attracting macrophages to the liver to promote inflammation and fibrosis.

Project description:Bone fragility fractures are caused by low bone mass or impaired bone quality. Osteoblast/osteoclast coordination determines bone mass, but the factors that control bone quality are poorly understood. Osteocytes regulate osteoblast and osteoclast activity on bone surfaces but can also directly reorganize the bone matrix to improve bone quality through perilacunar/canalicular remodeling; however, the molecular mechanisms remain unclear. We previously found that deleting the transcriptional regulators Yes-associated protein (YAP) and transcriptional co-activator with PDZ-motif (TAZ) from osteoblast-lineage cells caused lethality in mice due to skeletal fragility. Here, we tested the hypothesis that YAP and TAZ regulate osteocyte-mediated bone remodeling by conditional ablation of both YAP and TAZ from mouse osteocytes using 8 kb-DMP1-Cre. Osteocyte-conditional YAP/TAZ deletion reduced bone mass and dysregulated matrix collagen content and organization, which together decreased bone mechanical properties. Further, YAP/TAZ deletion impaired osteocyte perilacunar/canalicular remodeling by reducing canalicular network density, length, and branching, as well as perilacunar flourochrome-labeled mineral deposition. Consistent with recent studies identifying TGF-β as a key inducer of osteocyte expression of matrix-remodeling enzymes, YAP/TAZ deletion in vivo decreased osteocyte expression of matrix proteases MMP13, MMP14, and CTSK. In vitro, pharmacologic inhibition of YAP/TAZ transcriptional activity in osteocyte-like cells abrogated TGF-β-induced matrix protease gene expression. Together, these data show that YAP and TAZ control bone matrix accrual, organization, and mechanical properties by regulating osteocyte-mediated bone remodeling. Elucidating the signaling pathways that control perilacunar/canalicular remodeling may enable future therapeutic targeting of bone quality to reverse skeletal fragility. © 2019 American Society for Bone and Mineral Research.

Dataset Information

Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) mediate cell density-dependent proinflammatory responses.

Publications

Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) mediate cell density-dependent proinflammatory responses.

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