GLS1聚集成杆状结构促进谷氨酰胺饥饿诱导的细胞凋亡

谷氨酰胺是人体内含量最丰富的自由氨基酸，也是生物合成中碳源和氮源的重要提供者，多数肿瘤细胞的生长和增殖依赖于谷氨酰胺代谢，缺乏谷氨酰胺会引起细胞凋亡，其机理还所知甚少。谷氨酰胺酶（GLS1）是谷氨酰胺代谢的关键酶，然而我们发现在多种肿瘤细胞中敲除GLS1反而能抑制谷氨酰胺饥饿诱导的细胞凋亡，说明GLS1能促进谷氨酰胺缺乏诱导的细胞凋亡。通过免疫荧光染色，我们惊奇地发现在谷氨酰胺饥饿状态下GLS1能聚集成杆状的超级结构，且这种超级结构的形成是GLS1促凋亡的关键因素。进一步研究发现GLS1形成的超级结构能急剧上调ROS，促进 BAX的线粒体转运，从而触发凋亡。在该项目中我们拟进一步研究谷氨酰胺缺乏引起GLS1聚集成超级结构；GLS1超级结构上调ROS及ROS促进BAX的线粒体转运并最终引起细胞凋亡的机理。我们的研究将揭示GLS1的多功能性，并阐明一个新的谷氨酰胺饥饿诱导的细胞凋亡的机理。

Glutamine，the most abundant free amino acid in humans，is an important nitrogen and carbon donor. Most tumor cell lines consume large quantities glutamine to support cell growth and proliferation．Mass evidences have highlighted glutamine deprivation can induce apoptosis. However, the detail mechanism underline glutamine deprivation mediated cell death is not well understood. Our preliminary work showed that knock-out GLS1, a key enzyme in glutamine metabolism, dramatically suppressed apoptotic cell death in a variaty of cell lines. By employing immunofluorescent staining, we surprisedly found that GLS1 could assemble into a fiber like oligomer and this higher order structure played an important role in glutamine deprivation mediated cell death. Further study showed that GLS1 high order oligomer facilitated the accumulation of ROS and translocation of BAX to mitochondria. We will try to clarify the mechanism how GLS1 assemble into a fiber like oligomer under glutamine deprivation. We will also try to figure out how this high order structure upregulates ROS and facilitates translocation of BAX to mitochondria to promote cell death. Our study will clarify a new function of GLS1 and provide new insignt into glutamine deprivation mediated cell death.