2. Academic Validation
  3. 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

  • J Biol Chem. 2018 Nov 23;293(47):18071-18085. doi: 10.1074/jbc.RA118.004251.
Qiong Zhang 1,  Xu Han 2,  Jinfeng Chen 3,  Xiaomei Xie 4,  Jiafeng Xu 2,  Yang Zhao 2,  Jie Shen 5,  Lin Hu 6,  Pinglong Xu 2,  Hai Song 2,  Long Zhang 2,  Bin Zhao 2,  Ying-Jie Wang 7,  Zongping Xia 8
Affiliations

Affiliations

  • 1 From the Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, 310058 Zhejiang, China,; Translational Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan, China,; State Key Laboratory for Diagnosis and Treatment of Infectious Diseases and.
  • 2 From the Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, 310058 Zhejiang, China.
  • 3 Translational Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan, China.
  • 4 From the Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, 310058 Zhejiang, China,; Youth League Committee of Zhejiang Gongshang University, Hangzhou, 310018 Zhejiang, China, and.
  • 5 Department of Medical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003 Zhejiang, China.
  • 6 Institutes of Biology and Medical Sciences, Soochow University, Suzhou, 215000 Jiangsu, China.
  • 7 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases and.
  • 8 From the Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, 310058 Zhejiang, China,; Translational Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan, China,. Electronic address: zxia2018@zzu.edu.cn.
PMID: 30315101 DOI: 10.1074/jbc.RA118.004251
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-κΒ activation through the proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor α (TNFα) is not affected by cell density. However, we also noted that specific NF-κΒ 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-1β 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.

Keywords

COX-2; Hippo pathway; NF-κB; TAZ; TEADs; Yes-associated protein (YAP); cell signaling; cytokine; histone deacetylase (HDAC); inflammation.

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