Glutamine deprivation initiates reversible assembly of mammalian rods and rings
Glutamine deprivation initiates reversible assembly of mammalian rods and rings
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DOI：
10.1007/s00018-014-1567-6
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发表时间：
2014-08-01
影响因子：
8
通讯作者：
Chan, Edward K. L.
中科院分区：
文献类型：
--
作者：
Calise, S. John;Carcamo, Wendy C.;Chan, Edward K. L.
杆状和环状结构（RR）是由CTP和GTP生物合成的关键酶--胞苷三磷酸合成酶1（CTPS 1）和肌苷一磷酸脱氢酶2（IMPDH 2）组成的蛋白质组装体。CTPS 1或IMPDH 2的小分子抑制剂在15分钟至数小时内诱导各种癌细胞系中的RR组装。由于谷氨酰胺是这些核苷酸生物合成途径中必需的酰胺氮供体，因此检查谷氨酰胺剥夺以确定其是否导致RR形成。在正常条件下培养的HeLa细胞不显示RR，但在缺乏谷氨酰胺的培养基中培养后，24小时后形成短杆（< 2 μ m），48小时后形成长杆（> 5 μ m）。补充谷氨酰胺或鸟苷后，这些RR在15分钟内几乎完全解体。谷氨酰胺合成酶与蛋氨酸亚砜亚胺的抑制也增加了RR大会在细胞中剥夺谷氨酰胺。总之，我们的数据支持的假设，CTP/GTP生物合成酶的抑制剂，以形成RR响应谷氨酰胺的细胞内水平降低。我们推测，杆和环的形成是一种适应性代谢反应与破坏谷氨酰胺稳态。
Rods and rings (RR) are protein assemblies composed of cytidine triphosphate synthetase type 1 (CTPS1) and inosine monophosphate dehydrogenase type 2 (IMPDH2), key enzymes in CTP and GTP biosynthesis. Small-molecule inhibitors of CTPS1 or IMPDH2 induce RR assembly in various cancer cell lines within 15 min to hours. Since glutamine is an essential amide nitrogen donor in these nucleotide biosynthetic pathways, glutamine deprivation was examined to determine whether it leads to RR formation. HeLa cells cultured in normal conditions did not show RR, but after culturing in media lacking glutamine, short rods (< 2 mu m) assembled after 24 h, and longer rods (> 5 mu m) formed after 48 h. Upon supplementation with glutamine or guanosine, these RR underwent almost complete disassembly within 15 min. Inhibition of glutamine synthetase with methionine sulfoximine also increased RR assembly in cells deprived of glutamine. Taken together, our data support the hypothesis that CTP/GTP biosynthetic enzymes polymerize to form RR in response to a decreased intracellular level of glutamine. We speculate that rod and ring formation is an adaptive metabolic response linked to disruption of glutamine homeostasis.