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

Author:

Tanaka Masato,Shirakura KeisukeORCID,Takayama Yui,Μatsui Miki,Watanabe Yukio,Yamamoto TakuyaORCID,Takahashi Junya,Tanaka Shota,Hino Nobumasa,Doi Takefumi,Obana MasanoriORCID,Fujio Yasushi,Takayama KazuoORCID,Okada YoshiakiORCID

Abstract

AbstractAccumulating 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.

Funder

MEXT | Japan Society for the Promotion of Science

Japan Agency for Medical Research and Development

Japan Research Foundation for Clinical Pharmacology

Mochida Memorial Foundation for Medical and Pharmaceutical Research

Takeda Science Foundation

Publisher

Springer Science and Business Media LLC

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