Role of glutamine synthetase in angiogenesis beyond glutamine synthesis

Nature. 2018 Sep;561(7721):63-69. doi: 10.1038/s41586-018-0466-7.

Guy Eelen ¹ ² ³, Charlotte Dubois ⁴ ⁵, Anna Rita Cantelmo ⁴ ⁵ ⁶, Jermaine Goveia ⁴ ⁵, Ulrike Brüning ⁴ ⁵ ⁷, Michael DeRan ⁸, Gopala Jarugumilli ⁸, Jos van Rijssel ⁹, Giorgio Saladino ¹⁰, Federico Comitani ¹⁰, Annalisa Zecchin ⁴ ⁵, Susana Rocha ¹¹, Rongyuan Chen ¹², Hongling Huang ⁴ ⁵ ¹³, Saar Vandekeere ⁴ ⁵, Joanna Kalucka ⁴ ⁵, Christian Lange ⁴ ⁵ ¹⁴, Francisco Morales-Rodriguez ⁴ ⁵, Bert Cruys ⁴ ⁵, Lucas Treps ⁴ ⁵, Leanne Ramer ⁴ ⁵ ¹⁵, Stefan Vinckier ⁴ ⁵, Katleen Brepoels ⁴ ⁵, Sabine Wyns ⁴ ⁵, Joris Souffreau ⁴ ⁵, Luc Schoonjans ⁴ ⁵, Wouter H Lamers ¹⁶, Yi Wu ¹⁷, Jurgen Haustraete ¹⁸ ¹⁹, Johan Hofkens ¹¹, Sandra Liekens ²⁰, Richard Cubbon ⁴ ⁵ ²¹, Bart Ghesquière ²², Mieke Dewerchin ⁴ ⁵, Francesco L Gervasio ¹⁰ ²³, Xuri Li ²⁴, Jaap D van Buul ⁹, Xu Wu ⁸, Peter Carmeliet ²⁵ ²⁶ ²⁷

Affiliations

1 Center for Cancer Biology, University of Leuven, Leuven, Belgium. [email protected].
2 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, China. [email protected].
3 Center for Cancer Biology, VIB, Leuven, Belgium. [email protected].
4 Center for Cancer Biology, University of Leuven, Leuven, Belgium.
5 Center for Cancer Biology, VIB, Leuven, Belgium.
6 Université de Lille, INSERM U1003, Physiologie Cellulaire, Lille, France.
7 Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
8 Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
9 Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
10 Department of Chemistry, University College London, London, UK.
11 Molecular Imaging and Photonics, University of Leuven, Leuven, Belgium.
12 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, China.
13 Immunology Department, St. Jude Children's Research Hospital, Memphis, TN, USA.
14 DFG-Research Center for Regenerative Therapies, Technical University Dresden, Dresden, Germany.
15 Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada.
16 Tytgat Institute for Liver and Gastrointestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
17 Center for Cell Analyses and Modelling, University of Connecticut Health Centre, Farmington, CT, USA.
18 Inflammation Research Center, VIB, Ghent, Belgium.
19 Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
20 Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium.
21 Division of Cardiovascular and Diabetes Research, Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, UK.
22 Metabolomics Core Facility, Center for Cancer Biology, VIB, Leuven, Belgium.
23 Institute of Structural Molecular Biology, University College London, London, UK.
24 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, China. [email protected].
25 Center for Cancer Biology, University of Leuven, Leuven, Belgium. [email protected].
26 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, China. [email protected].
27 Center for Cancer Biology, VIB, Leuven, Belgium. [email protected].

PMID: 30158707 DOI: 10.1038/s41586-018-0466-7

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.

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