Cytosolic GDH1 degradation restricts protein synthesis to sustain tumor cell survival following amino acid deprivation
Cytosolic GDH1 degradation restricts protein synthesis to sustain tumor cell survival following amino acid deprivation
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胞质 GDH1 降解限制蛋白质合成以维持氨基酸剥夺后肿瘤细胞的存活
DOI：
10.15252/embj.2020107480
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发表时间：
2021-07-16
期刊：
影响因子：
11.4
通讯作者：
Wang, Xiongjun
中科院分区：
文献类型：
--
作者：
Shao, Jialiang;Shi, Tiezhu;Wang, Xiongjun
mTORC 1通路在调节各种生物过程中起关键作用，包括感知氨基酸剥夺和驱动核糖体蛋白（RP）编码基因的表达。在这项研究中，我们观察到谷氨酸脱氢酶1（GDH 1），一种将谷氨酸转化为α-酮戊二酸（α KG）的酶，对肾脏肾透明细胞癌（KIRC）细胞的氨基酸剥夺产生抗性。从机制上讲，在足够营养的条件下，GDH1以依赖于其酶活性的方式维持RP基因表达。在氨基酸剥夺或mTORC 1抑制后，GDH 1从线粒体易位到细胞质，在那里它变得泛素化并通过E3连接酶RNF213降解。GDH1降解使细胞内α KG水平降低一半以上，并降低α KG依赖性赖氨酸脱甲基酶（KDM）的活性。降低的KDM活性反过来导致组蛋白H3赖氨酸9和27甲基化增加，进一步抑制RP基因表达并保留营养以支持细胞存活。总之，我们的研究证实了实体瘤细胞应对氨基酸缺乏的经济有效的策略，这可能在未来有针对性地阻止肾癌进展。
The mTORC1 pathway plays key roles in regulating various biological processes, including sensing amino acid deprivation and driving expression of ribosomal protein (RP)-coding genes. In this study, we observed that depletion of glutamate dehydrogenase 1 (GDH1), an enzyme that converts glutamate to alpha-ketoglutarate (alpha KG), confers resistance to amino acid deprivation on kidney renal clear cell carcinoma (KIRC) cells. Mechanistically, under conditions of adequate nutrition, GDH1 maintains RP gene expression in a manner dependent on its enzymatic activity. Following amino acid deprivation or mTORC1 inhibition, GDH1 translocates from mitochondria to the cytoplasm, where it becomes ubiquitinated and degraded via the E3 ligase RNF213. GDH1 degradation reduces intracellular alpha KG levels by more than half and decreases the activity of alpha KG-dependent lysine demethylases (KDMs). Reduced KDM activity in turn leads to increased histone H3 lysine 9 and 27 methylation, further suppressing RP gene expression and preserving nutrition to support cell survival. In summary, our study exemplifies an economical and efficient strategy of solid tumor cells for coping with amino acid deficiency, which might in the future be targeted to block renal carcinoma progression.