谷氨酰胺分解代谢增强是癌症的主要代谢特征之一，为癌症进展提供能量和中间代谢产物。然而，营养剥夺下谷氨酰胺分解代谢在癌症中的功能需要进一步阐明。在这里，我们发现谷氨酸脱氢酶 1 (GLUD1) 是谷氨酰胺分解代谢的关键酶之一，其脱乙酰化可通过抑制自噬性细胞死亡来维持葡萄糖饥饿下肺腺癌细胞 (LUAD) 的存活。我们发现葡萄糖饥饿通过减少 Lys84 上的乙酰化来增加 GLUD1 的活性，并促进其活性六聚体的形成。此外，GLUD1 的去乙酰化诱导其细胞质定位，其中 GLUD1 在 K63 连接中被 TRIM21 泛素化，导致 GLUD1 与细胞质谷氨酰胺酶 KGA 结合。这两种作用增强了线粒体和细胞质中的谷氨酰胺代谢，增加了α-酮戊二酸（α-KG）的产生。同时，细胞质GLUD1也与p62相互作用并阻止其乙酰化，从而抑制p62体的形成。所有这些作用都阻止了葡萄糖饥饿下 LUAD 细胞的自噬细胞死亡。总而言之，我们的结果揭示了 LUAD 细胞中葡萄糖剥夺下 GLUD1 的新功能，并为癌症进展过程中谷氨酰胺分解代谢的功能提供了新的见解。© 2024 作者。

Enhanced glutamine catabolism is one of the main metabolic features of cancer, providing energy and intermediate metabolites for cancer progression. However, the functions of glutamine catabolism in cancer under nutrient deprivation need to be further clarified. Here, we discovered that deacetylation of glutamate dehydrogenase 1 (GLUD1), one of the key enzymes in glutamine catabolism, maintains the survival of lung adenocarcinoma (LUAD) cells under glucose starvation by inhibiting autophagic cell death. We found that glucose starvation increased GLUD1 activity by reducing its acetylation on Lys84 and promoted its active hexamer formation. Besides, deacetylation of GLUD1 induced its cytoplasmic localization, where GLUD1 was ubiquitinated in K63-linkage by TRIM21, leading to the binding of GLUD1 with cytoplasmic glutaminase KGA. These two effects enhanced glutamine metabolism both in mitochondria and cytoplasm, increased the production of alpha-ketoglutarate (α-KG). Meanwhile, cytoplasmic GLUD1 also interacted with p62 and prevented its acetylation, leading to the inhibition of p62 body formation. All these effects blocked autophagic cell death of LUAD cells under glucose starvation. Taken together, our results reveal a novel function of GLUD1 under glucose deprivation in LUAD cells and provide new insights into the functions of glutamine catabolism during cancer progression.© 2024 The Authors.