SUCLA2-coupled regulation of GLS succinylation and activity counteracts oxidative stress in tumor cells

• Published in: Molecular cell 2021-06, Vol.81 (11), p.2303-2316.e8
• Main Authors: Tong, Yingying, Guo, Dong, Lin, Shu-Hai, Liang, Jiazhen, Yang, Dianqiang, Ma, Chunmin, Shao, Fei, Li, Min, Yu, Qiujing, Jiang, Yuhui, Li, Lei, Fang, Jing, Yu, Rilei, Lu, Zhimin
• Format: Article
• Language: English
• Subjects: GLS; glutaminolysis; GSH; NADPH; p38; phosphorylation; succinyl-CoA; succinylation; SUCLA2; tumorigenesis
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2021.04.002

Glutaminase regulates glutaminolysis to promote cancer cell proliferation. However, the mechanism underlying glutaminase activity regulation is largely unknown. Here, we demonstrate that kidney-type glutaminase (GLS) is highly expressed in human pancreatic ductal adenocarcinoma (PDAC) specimens with correspondingly upregulated glutamine dependence for PDAC cell proliferation. Upon oxidative stress, the succinyl-coenzyme A (CoA) synthetase ADP-forming subunit β (SUCLA2) phosphorylated by p38 mitogen-activated protein kinase (MAPK) at S79 dissociates from GLS, resulting in enhanced GLS K311 succinylation, oligomerization, and activity. Activated GLS increases glutaminolysis and the production of nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione, thereby counteracting oxidative stress and promoting tumor cell survival and tumor growth in mice. In addition, the levels of SUCLA2 pS79 and GLS K311 succinylation, which were mutually correlated, were positively associated with advanced stages of PDAC and poor prognosis for patients. Our findings reveal critical regulation of GLS by SUCLA2-coupled GLS succinylation regulation and underscore the regulatory role of metabolites in glutaminolysis and PDAC development. •GLS is upregulated in human pancreatic ductal adenocarcinoma•GLS K311 succinylation enhances the oligomerization and activity of GLS•p38-phosphorylated SUCLA2 dissociates from GLS and promotes GLS K311 succinylation•GLS succinylation promotes glutaminolysis and tumor growth Tong et al. demonstrate that oxidative stress removes GLS-associated SUCLA2 to catalyze succinyl-CoA. This dissociation enhances succinyl-CoA-dependent GLS K311 succinylation and activity, leading to increased production of NADPH and GSH against oxidative-stress-induced ROS production and apoptosis and promoting tumor cell proliferation and tumor growth in mice.