2. Academic Validation
  3. Filamentous GLS1 promotes ROS-induced apoptosis upon glutamine deprivation via insufficient asparagine synthesis

Filamentous GLS1 promotes ROS-induced apoptosis upon glutamine deprivation via insufficient asparagine synthesis

  • Mol Cell. 2022 May 19;82(10):1821-1835.e6. doi: 10.1016/j.molcel.2022.03.016.
Bin Jiang 1,  Jia Zhang 1,  Guohui Zhao 1,  Mengjue Liu 1,  Jielu Hu 1,  Furong Lin 1,  Jinyang Wang 1,  Wentao Zhao 1,  Huanhuan Ma 1,  Cixiong Zhang 1,  Caiming Wu 1,  Luming Yao 1,  Qingfeng Liu 1,  Xin Chen 1,  Yating Cao 1,  Yi Zheng 1,  Chensong Zhang 1,  Aidong Han 1,  Donghai Lin 2,  Qinxi Li 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
  • 2 MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, Key Laboratory of Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, China.
  • 3 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. Electronic address: liqinxi@xmu.edu.cn.
PMID: 35381197 DOI: 10.1016/j.molcel.2022.03.016
Abstract

GLS1 orchestrates glutaminolysis and promotes cell proliferation when glutamine is abundant by regenerating TCA cycle intermediates and supporting redox homeostasis. CB-839, an inhibitor of GLS1, is currently under clinical investigation for a variety of Cancer types. Here, we show that GLS1 facilitates Apoptosis when glutamine is deprived. Mechanistically, the absence of exogenous glutamine sufficiently reduces glutamate levels to convert dimeric GLS1 to a self-assembled, extremely low-Km filamentous polymer. GLS1 filaments possess an enhanced catalytic activity, which further depletes intracellular glutamine. Functionally, filamentous GLS1-dependent glutamine scarcity leads to inadequate synthesis of asparagine and mitogenome-encoded proteins, resulting in ROS-induced Apoptosis that can be rescued by asparagine supplementation. Physiologically, we observed GLS1 filaments in solid tumors and validated the tumor-suppressive role of constitutively active, filamentous GLS1 mutants K320A and S482C in xenograft models. Our results change our understanding of GLS1 in Cancer metabolism and suggest the therapeutic potential of promoting GLS1 filament formation.

Keywords

apoptosis; glutaminase; glutamine metabolism.

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