Role of glutamine synthetase in angiogenesis beyond glutamine synthesis

Nature
Guy EelenPeter Carmeliet

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...Continue Reading

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Methods Mentioned

BETA
GTPase
pull-down
FRET
GTPases
biosensor
co-immunoprecipitation
immunoprecipitation
fluorescence microscopy
in silico methods
density-gradient centrifugation

Software Mentioned

Gromacs
XCalibur
Image Quant LAS 4000
ZEN
XF Reader
R
Leica MM AF
lme4
Basic Local Alignment Search Tool ( BLAST )
GraphPad Prism7

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