Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) mediate cell density-dependent proinflammatory responses
Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) mediate cell density-dependent proinflammatory responses
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Yes相关蛋白（YAP）和具有PDZ结合基序的转录共激活因子（TAZ）介导细胞密度依赖性促炎反应
DOI：
10.1074/jbc.ra118.004251
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发表时间：
2018-11-23
影响因子：
4.8
通讯作者：
Xia, Zongping
中科院分区：
文献类型：
--
作者：
Zhang, Qiong;Han, Xu;Xia, Zongping
适当的炎症反应对于损伤或感染后组织稳态的恢复至关重要，但这种反应如何受到细胞和组织微环境的物理性质的调节尚未完全了解。在这里，使用H358，HeLa和HEK 293 T细胞，我们报告细胞密度可以通过Hippo信号通路调节炎症反应。我们发现，通过促炎细胞因子白细胞介素-1（IL-1）和肿瘤坏死因子（TNF）激活NF-B不受细胞密度的影响。然而，我们也注意到，特定的NF-B靶基因，如环氧化酶2（考克斯-2），在低细胞密度下比在高细胞密度下诱导少得多。机制上，我们观察到转录辅激活因子Yes相关蛋白（雅普）和具有PDZ结合基序的转录辅激活因子（TAZ）定位于细胞核，与TEA结构域转录因子（TEAD）结合，将组蛋白脱乙酰酶7（HDAC 7）募集到考克斯-2的启动子区域，并在低细胞密度下抑制其转录，而高细胞密度消除了这种雅普/TAZ介导的转录抑制。值得注意的是，IL-1刺激主要通过考克斯-2诱导促进细胞迁移和侵袭，但雅普抑制这种诱导，从而抑制细胞迁移和侵袭。这些结果表明，雅普/TAZ-TEAD相互作用可以抑制考克斯-2的转录，从而介导细胞密度依赖性的促炎反应的调节。我们的研究结果强调了细胞微环境通过Hippo通路显著影响炎症反应。
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-B 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-B 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.