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

Tanaka, Masato; Shirakura, Keisuke; Takayama, Yui; Μatsui, Miki; Watanabe, Yukio; Yamamoto, Takuya; Takahashi, Junya; Tanaka, Shota; Hino, Nobumasa; Doi, Takefumi; Obana, Masanori; Fujio, Yasushi; Takayama, Kazuo; Okada, Yoshiaki

doi:https://doi.org/10.1038/s42003-024-06317-z

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

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

Communications Biology, 2024, 7, 599

アクセス数:1,464件（2025-06-30 14:17 集計）

固定URL: https://hdl.handle.net/11094/97222

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タイトル	Endothelial ROBO4 suppresses PTGS2/COX-2 expression and inflammatory diseases
著者	著者名 Tanaka, Masato
	著者名 Shirakura, Keisuke
	著者名 Takayama, Yui
	著者名 Μatsui, Miki
	著者名 Watanabe, Yukio
	NRID 1000060546993 1000060546993 著者名 Yamamoto, Takuya
	著者名 Takahashi, Junya
	NRID 1000080880294 1000080880294 researchmap permalink 80880294 80880294 Scopus Author ID 56612561000 56612561000 著者名 Tanaka, Shota
	NRID 1000090469916 1000090469916 ORCID 0000-0002-7072-1183 0000-0002-7072-1183 researchmap permalink crosslinker crosslinker Scopus Author ID 24175680600 24175680600 著者名 Hino, Nobumasa
	NRID 1000000211409 1000000211409 researchmap permalink read0014363 read0014363 Scopus Author ID 55525517900 55525517900 著者名 Doi, Takefumi
	NRID 1000050745883 1000050745883 researchmap permalink m_o m_o Scopus Author ID 17135691100 17135691100 著者名 Obana, Masanori
	NRID 1000020359839 1000020359839 ORCID 0000-0003-0828-2930 0000-0003-0828-2930 researchmap permalink yfujio yfujio Scopus Author ID 7006517527 7006517527 著者名 Fujio, Yasushi
	NRID 1000010759509 1000010759509 著者名 Takayama, Kazuo
	NRID 1000050444500 1000050444500 researchmap permalink magic_roundabout magic_roundabout Scopus Author ID 55721995000 55721995000 著者名 Okada, Yoshiaki
内容	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 .
抄録	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.
出版者	Nature Research
収録物名	Communications Biology
巻(号)	7
ページ	599
刊行年月	2024-05-18
言語	英語
ハンドルURL	https://hdl.handle.net/11094/97222
eISSN	23993642
関連情報 (isIdenticalTo)	DOI (出版社版) https://doi.org/10.1038/s42003-024-06317-z
アクセス権	open access
権利情報	This article is licensed under a Creative Commons Attribution 4.0 International License.
出版タイプ	Version of Record
カテゴリ	学術雑誌論文 Journal Article

資源タイプ	学術雑誌論文
ローカル資源タイプ	学術雑誌論文
DCTERMS.bibliographicCitation	Communications Biology. 2024, 7, p. 599
DC.title	Endothelial ROBO4 suppresses PTGS2/COX-2 expression and inflammatory diseases
DC.creator	Tanaka, Masato
	Shirakura, Keisuke
	Takayama, Yui
	Μatsui, Miki
	Watanabe, Yukio
	Yamamoto, Takuya
	Takahashi, Junya
	Tanaka, Shota
	Hino, Nobumasa
	Doi, Takefumi
	Obana, Masanori
	Fujio, Yasushi
	Takayama, Kazuo
	Okada, Yoshiaki
DC.publisher	Nature Research
DC.language' scheme='DCTERMS.RFC1766	英語
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2024-05-18
DC.identifier	https://doi.org/10.1038/s42003-024-06317-z
DC.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 .
DCTERMS.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.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	97222
citation_title	Endothelial ROBO4 suppresses PTGS2/COX-2 expression and inflammatory diseases
citation_author	Tanaka, Masato
	Shirakura, Keisuke
	Takayama, Yui
	Μatsui, Miki
	Watanabe, Yukio
	Yamamoto, Takuya
	Takahashi, Junya
	Tanaka, Shota
	Hino, Nobumasa
	Doi, Takefumi
	Obana, Masanori
	Fujio, Yasushi
	Takayama, Kazuo
	Okada, Yoshiaki
citation_publisher	Nature Research
citation_language	英語
citation_date	2024-05-18
citation_journal_title	Communications Biology
citation_volume	7
citation_firstpage	599
citation_doi	https://doi.org/10.1038/s42003-024-06317-z
citation_public_url	https://hdl.handle.net/11094/97222

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

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