Role of glutamine synthetase in angiogenesis beyond glutamine synthesis
- Author
- Guy Eelen, Charlotte Dubois, Anna Rita Cantelmo, Jermaine Goveia, Ulrike Bruning, Michael DeRan, Gopala Jarugumilli, Jos van Rijssel, Giorgio Saladino, Federico Comitani, Annalisa Zecchin, Susana Rocha, Rongyuan Chen, Hongling Huang, Saar Vandekeere, Joanna Kalucka, Christian Lange, Francisco Morales-Rodriguez, Bert Cruys, Lucas Treps, Leanne Ramer, Stefan Vinckier, Katleen Brepoels, Sabine Wyns, Joris Souffreau, Luc Schoonjans, Wouter H Lamers, Yi Wu, Jurgen Haustraete (UGent) , Johan Hofkens, Sandra Liekens, Richard Cubbon, Bart Ghesquiere, Mieke Dewerchin, Francesco L Gervasio, Xuri Li, Jaap D van Buul, Xu Wu and Peter Carmeliet
- Organization
- Abstract
- 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.
- Keywords
- RHO GTPASE, PROTEIN PALMITOYLATION, ENDOTHELIAL-CELLS, GLYCOLYSIS, VASCULATURE, DEFICIENCY, MIGRATION, JUNCTIONS, PATHWAY, MODEL
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Citation
Please use this url to cite or link to this publication: http://hdl.handle.net/1854/LU-8582947
- MLA
- Eelen, Guy, et al. “Role of Glutamine Synthetase in Angiogenesis beyond Glutamine Synthesis.” NATURE, vol. 561, no. 7721, 2018, pp. 63–69, doi:10.1038/s41586-018-0466-7.
- APA
- Eelen, G., Dubois, C., Cantelmo, A. R., Goveia, J., Bruning, U., DeRan, M., … Carmeliet, P. (2018). Role of glutamine synthetase in angiogenesis beyond glutamine synthesis. NATURE, 561(7721), 63–69. https://doi.org/10.1038/s41586-018-0466-7
- Chicago author-date
- Eelen, Guy, Charlotte Dubois, Anna Rita Cantelmo, Jermaine Goveia, Ulrike Bruning, Michael DeRan, Gopala Jarugumilli, et al. 2018. “Role of Glutamine Synthetase in Angiogenesis beyond Glutamine Synthesis.” NATURE 561 (7721): 63–69. https://doi.org/10.1038/s41586-018-0466-7.
- Chicago author-date (all authors)
- Eelen, Guy, Charlotte Dubois, Anna Rita Cantelmo, Jermaine Goveia, Ulrike Bruning, Michael DeRan, Gopala Jarugumilli, Jos van Rijssel, Giorgio Saladino, Federico Comitani, Annalisa Zecchin, Susana Rocha, Rongyuan Chen, Hongling Huang, Saar Vandekeere, Joanna Kalucka, Christian Lange, Francisco Morales-Rodriguez, Bert Cruys, Lucas Treps, Leanne Ramer, Stefan Vinckier, Katleen Brepoels, Sabine Wyns, Joris Souffreau, Luc Schoonjans, Wouter H Lamers, Yi Wu, Jurgen Haustraete, Johan Hofkens, Sandra Liekens, Richard Cubbon, Bart Ghesquiere, Mieke Dewerchin, Francesco L Gervasio, Xuri Li, Jaap D van Buul, Xu Wu, and Peter Carmeliet. 2018. “Role of Glutamine Synthetase in Angiogenesis beyond Glutamine Synthesis.” NATURE 561 (7721): 63–69. doi:10.1038/s41586-018-0466-7.
- Vancouver
- 1.Eelen G, Dubois C, Cantelmo AR, Goveia J, Bruning U, DeRan M, et al. Role of glutamine synthetase in angiogenesis beyond glutamine synthesis. NATURE. 2018;561(7721):63–9.
- IEEE
- [1]G. Eelen et al., “Role of glutamine synthetase in angiogenesis beyond glutamine synthesis,” NATURE, vol. 561, no. 7721, pp. 63–69, 2018.
@article{8582947,
abstract = {{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.}},
author = {{Eelen, Guy and Dubois, Charlotte and Cantelmo, Anna Rita and Goveia, Jermaine and Bruning, Ulrike and DeRan, Michael and Jarugumilli, Gopala and van Rijssel, Jos and Saladino, Giorgio and Comitani, Federico and Zecchin, Annalisa and Rocha, Susana and Chen, Rongyuan and Huang, Hongling and Vandekeere, Saar and Kalucka, Joanna and Lange, Christian and Morales-Rodriguez, Francisco and Cruys, Bert and Treps, Lucas and Ramer, Leanne and Vinckier, Stefan and Brepoels, Katleen and Wyns, Sabine and Souffreau, Joris and Schoonjans, Luc and Lamers, Wouter H and Wu, Yi and Haustraete, Jurgen and Hofkens, Johan and Liekens, Sandra and Cubbon, Richard and Ghesquiere, Bart and Dewerchin, Mieke and Gervasio, Francesco L and Li, Xuri and van Buul, Jaap D and Wu, Xu and Carmeliet, Peter}},
issn = {{0028-0836}},
journal = {{NATURE}},
keywords = {{RHO GTPASE,PROTEIN PALMITOYLATION,ENDOTHELIAL-CELLS,GLYCOLYSIS,VASCULATURE,DEFICIENCY,MIGRATION,JUNCTIONS,PATHWAY,MODEL}},
language = {{eng}},
number = {{7721}},
pages = {{63--69}},
title = {{Role of glutamine synthetase in angiogenesis beyond glutamine synthesis}},
url = {{http://doi.org/10.1038/s41586-018-0466-7}},
volume = {{561}},
year = {{2018}},
}
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