非经典的谷氨酸半胱氨酸连接酶活性可以阻止铁

作者：张馨予

本期文章：《细胞—代谢》：Online/在线发表

美国莫菲特癌症中心Gina M. DeNicola研究团队发现，非经典的谷氨酸半胱氨酸连接酶活性可以阻止铁死亡。这一研究成果于2020年12月23日在线发表在国际学术期刊《细胞—代谢》上。

研究人员发现，非小细胞肺癌细胞系的胱氨酸饥饿诱导了γ-谷氨酰胺肽的意外积累，这是由于谷氨酸-半胱氨酸连接酶催化亚基（GCLC）的非经典活性而产生的。此活性富集在高水平NRF2（GCLC的关键转录调节因子）的细胞系中，但在半胱氨酸受限后在健康的鼠类组织中也可诱导。

γ-谷氨酰肽的合成限制了谷氨酸的积累，从而防止了铁死亡。这些结果表明，GCLC通过在胱氨酸饥饿下维持谷氨酸稳态而在保护铁死亡中具有与谷胱甘肽无关的非经典作用。

研究人员介绍，半胱氨酸是维持正常细胞和转化细胞中细胞氧化还原稳态所必需的。剥夺半胱氨酸会导致铁依赖的细胞死亡形式，称为铁死亡。然而，半胱氨酸饥饿的代谢后果超出了谷胱甘肽合成受损的影响，其背后的原因目前尚不明确。

附：英文原文

Title: Non-canonical Glutamate-Cysteine Ligase Activity Protects against Ferroptosis

Author: Yun Pyo Kang, Andrea Mockabee-Macias, Chang Jiang, Aimee Falzone, Nicolas Prieto-Farigua, Everett Stone, Isaac S. Harris, Gina M. DeNicola

Issue&Volume: 2020-12-23

Abstract: Cysteine is required for maintaining cellular redox homeostasis in both normal andtransformed cells. Deprivation of cysteine induces the iron-dependent form of celldeath known as ferroptosis; however, the metabolic consequences of cysteine starvationbeyond impairment of glutathione synthesis are poorly characterized. Here, we findthat cystine starvation of non-small-cell lung cancer cell lines induces an unexpectedaccumulation of γ-glutamyl-peptides, which are produced due to a non-canonical activityof glutamate-cysteine ligase catalytic subunit (GCLC). This activity is enriched incell lines with high levels of NRF2, a key transcriptional regulator of GCLC, butis also inducible in healthy murine tissues following cysteine limitation. γ-glutamyl-peptidesynthesis limits the accumulation of glutamate, thereby protecting against ferroptosis.These results indicate that GCLC has a glutathione-independent, non-canonical rolein the protection against ferroptosis by maintaining glutamate homeostasis under cystinestarvation.

DOI: 10.1016/j.cmet.2020.12.007

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30662-8

期刊信息

Cell Metabolism：《细胞—代谢》，创刊于2005年。隶属于细胞出版社，最新IF：22.415
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