Journal
NATURE
Volume 561, Issue 7721, Pages 63-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41586-018-0466-7
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Funding
- FWO
- LERN/FDRS
- IWT
- Marie Curie-IEF Fellowship
- EMBO Long-Term Fellowship
- LSBR fellowship
- British Heart Foundation Intermediate Clinical Fellowship
- American Cancer Society RSG
- NIH/NCI
- NIH/NIDDK
- EPSRC
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center at Sun Yat-Sen University
- National Natural Science Foundation of China [81330021, 81670855]
- Federal Government Belgium
- Flemish Government, a Concerted Research Activities Belgium grant
- Foundation against Cancer
- ERC Advanced Research Grant
- EPSRC [EP/L000253/1, EP/P011306/1] Funding Source: UKRI
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Glutamine synthetase, encoded by the gene GLUL, is an enzyme that converts glutamate and ammonia to glutamine. It is expressed by endothelial cells, but surprisingly shows negligible glutamine-synthesizing activity in these cells at physiological glutamine levels. Here we show in mice that genetic deletion of Glul in endothelial cells impairs vessel sprouting during vascular development, whereas pharmacological blockade of glutamine synthetase suppresses angiogenesis in ocular and inflammatory skin disease while only minimally affecting healthy adult quiescent endothelial cells. This relies on the inhibition of endothelial cell migration but not proliferation. Mechanistically we show that in human umbilical vein endothelial cells GLUL knockdown reduces membrane localization and activation of the GTPase RHOJ while activating other Rho GTPases and Rho kinase, thereby inducing actin stress fibres and impeding endothelial cell motility. Inhibition of Rho kinase rescues the defect in endothelial cell migration that is induced by GLUL knockdown. Notably, glutamine synthetase palmitoylates itself and interacts with RHOJ to sustain RHOJ palmitoylation, membrane localization and activation. These findings reveal that, in addition to the known formation of glutamine, the enzyme glutamine synthetase shows unknown activity in endothelial cell migration during pathological angiogenesis through RHOJ palmitoylation.
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