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.The enzyme glutamine synthetase is active in endothelial cell migration during angiogenesis, through autopalmitoylation and the regulation of RHOJ signalling.

中文翻译：

---

谷氨酰胺合成酶在谷氨酰胺合成以外的血管生成中的作用

由基因 GLUL 编码的谷氨酰胺合成酶是一种将谷氨酸和氨转化为谷氨酰胺的酶。它由内皮细胞表达，但令人惊讶的是，在生理谷氨酰胺水平下，这些细胞中的谷氨酰胺合成活性可忽略不计。在这里，我们在小鼠中表明，内皮细胞中 Glul 的基因缺失会损害血管发育过程中的血管萌发，而谷氨酰胺合成酶的药理学阻断抑制眼部和炎症性皮肤病中的血管生成，同时对健康成年静止内皮细胞的影响很小。这依赖于对内皮细胞迁移而非增殖的抑制。我们从机制上表明，在人脐静脉内皮细胞中，GLUL 敲低会降低 GTPase RHOJ 的膜定位和激活，同时激活其他 Rho GTPases 和 Rho 激酶，从而诱导肌动蛋白应力纤维并阻碍内皮细胞运动。抑制 Rho 激酶可挽救由 GLUL 敲低诱导的内皮细胞迁移缺陷。值得注意的是，谷氨酰胺合成酶自身棕榈酰化并与 RHOJ 相互作用以维持 RHOJ 棕榈酰化、膜定位和激活。这些发现表明，除了已知的谷氨酰胺形成外，谷氨酰胺合成酶在通过 RHOJ 棕榈酰化的病理性血管生成过程中在内皮细胞迁移中显示出未知的活性。谷氨酰胺合成酶在血管生成过程中对内皮细胞迁移具有活性，