Endothelial ROBO4 suppresses PTGS2/COX-2 expression and inflammatory diseases

Tanaka, Masato; Shirakura, Keisuke; Takayama, Yui et al.

Communications Biology, 2024, 7, 599

Number of Access:1,934（2025-07-27 21:02 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/97222

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Title
Endothelial ROBO4 suppresses PTGS2/COX-2 expression and inflammatory diseases
Creator
CreatorName
Tanaka, Masato
CreatorName
Shirakura, Keisuke
CreatorName
Takayama, Yui
CreatorName
Μatsui, Miki
CreatorName
Watanabe, Yukio
NRID
1000060546993 1000060546993
CreatorName
Yamamoto, Takuya
CreatorName
Takahashi, Junya
NRID
1000080880294 1000080880294
researchmap permalink
80880294 80880294
Scopus Author ID
56612561000 56612561000
CreatorName
Tanaka, Shota
NRID
1000090469916 1000090469916
ORCID
0000-0002-7072-1183 0000-0002-7072-1183
researchmap permalink
crosslinker crosslinker
Scopus Author ID
24175680600 24175680600
CreatorName
Hino, Nobumasa
NRID
1000000211409 1000000211409
researchmap permalink
read0014363 read0014363
Scopus Author ID
55525517900 55525517900
CreatorName
Doi, Takefumi
NRID
1000050745883 1000050745883
researchmap permalink
m_o m_o
Scopus Author ID
17135691100 17135691100
CreatorName
Obana, Masanori
NRID
1000020359839 1000020359839
ORCID
0000-0003-0828-2930 0000-0003-0828-2930
researchmap permalink
yfujio yfujio
Scopus Author ID
7006517527 7006517527
CreatorName
Fujio, Yasushi
NRID
1000010759509 1000010759509
CreatorName
Takayama, Kazuo
NRID
1000050444500 1000050444500
researchmap permalink
magic_roundabout magic_roundabout
Scopus Author ID
55721995000 55721995000
CreatorName
Okada, Yoshiaki
Description
Tanaka M., Shirakura K., Takayama Y., et al. Endothelial ROBO4 suppresses PTGS2/COX-2 expression and inflammatory diseases. Communications Biology 7, 599 (2024); https://doi.org/10.1038/s42003-024-06317-z .
Abstract
Accumulating evidence suggests that endothelial cells can be useful therapeutic targets. One of the potential targets is an endothelial cell-specific protein, Roundabout4 (ROBO4). ROBO4 has been shown to ameliorate multiple diseases in mice, including infectious diseases and sepsis. However, its mechanisms are not fully understood. In this study, using RNA-seq analysis, we found that ROBO4 downregulates prostaglandin-endoperoxide synthase 2 (PTGS2), which encodes cyclooxygenase-2. Mechanistic analysis reveals that ROBO4 interacts with IQ motif-containing GTPase-activating protein 1 (IQGAP1) and TNF receptor-associated factor 7 (TRAF7), a ubiquitin E3 ligase. In this complex, ROBO4 enhances IQGAP1 ubiquitination through TRAF7, inhibits prolonged RAC1 activation, and decreases PTGS2 expression in inflammatory endothelial cells. In addition, Robo4-deficiency in mice exacerbates PTGS2-associated inflammatory diseases, including arthritis, edema, and pain. Thus, we reveal the molecular mechanism by which ROBO4 suppresses the inflammatory response and vascular hyperpermeability, highlighting its potential as a promising therapeutic target for inflammatory diseases.
Publisher
Nature Research
Source Title
Communications Biology
Volume (Issue)
7
Page
599
Date of Issued
2024-05-18
Language
English
Handle URL
https://hdl.handle.net/11094/97222
eISSN
23993642
Relation.isIdenticalTo
DOI (Publisher Version)
https://doi.org/10.1038/s42003-024-06317-z
Access Rights
open access
CopyRight
This article is licensed under a Creative Commons Attribution 4.0 International License.
oaire:version
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Category
学術雑誌論文 Journal Article