<br>SUCLG2 通过琥珀酰化调节肺腺癌中的线粒体功能障碍,Advanced Science

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SUCLG2 通过琥珀酰化调节肺腺癌中的线粒体功能障碍
Advanced Science ( IF 14.3 ) Pub Date : 2023-10-30 , DOI: 10.1002/advs.202303535
Qifan Hu _{1,

2,

3} , Jing Xu ₂ , Lei Wang ₂ , Yi Yuan ₄ , Ruiguang Luo ₂ , Mingxi Gan ₂ , Keru Wang ₄ , Tao Zhao ₂ , Yawen Wang ₂ , Tianyu Han _{3,

5,

6} , Jian-Bin Wang _{1,

2}

Affiliation

线粒体功能障碍和能量代谢异常是癌症的主要特征。然而，癌症进展过程中线粒体功能障碍的机制尚不清楚。在此，证明琥珀酰辅酶 A (CoA) 合成酶 GDP 形成亚基 β (SUCLG2) 的表达水平可以影响肺腺癌细胞 (LUAD) 的整体琥珀酰化。琥珀酰组分析表明，SUCLG2 的缺失可以上调线粒体蛋白的琥珀酰化水平，并通过降低酶活性或蛋白质稳定性来抑制关键代谢酶的功能，从而抑制 LUAD 细胞中的线粒体功能。有趣的是，SUCLG2本身在Lys93上也发生琥珀酰化，这种琥珀酰化增强了其蛋白质稳定性，导致SUCLG2上调，促进LUAD细胞的增殖和肿瘤发生。 Sirtuin 5 (SIRT5) 在 Lys93 上使 SUCLG2 去琥珀酰化，然后通过 K63 连接和溶酶体中的降解，包含三联基序的蛋白 21 (TRIM21) 介导的泛素化。该研究结果揭示了SUCLG2在线粒体功能障碍中的新作用，并阐明了SUCLG2在LUAD中琥珀酰化介导的蛋白稳态机制，从而为开发针对SUCLG2的抗癌药物提供了理论基础。

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SUCLG2 Regulates Mitochondrial Dysfunction through Succinylation in Lung Adenocarcinoma

Mitochondrial dysfunction and abnormal energy metabolism are major features of cancer. However, the mechanisms underlying mitochondrial dysfunction during cancer progression are far from being clarified. Here, it is demonstrated that the expression level of succinyl-coenzyme A (CoA) synthetase GDP-forming subunit β (SUCLG2) can affect the overall succinylation of lung adenocarcinoma (LUAD) cells. Succinylome analysis shows that the deletion of SUCLG2 can upregulate the succinylation level of mitochondrial proteins and inhibits the function of key metabolic enzymes by reducing either enzymatic activity or protein stability, thus dampening mitochondrial function in LUAD cells. Interestingly, SUCLG2 itself is also succinylated on Lys93, and this succinylation enhances its protein stability, leading to the upregulation of SUCLG2 and promoting the proliferation and tumorigenesis of LUAD cells. Sirtuin 5 (SIRT5) desuccinylates SUCLG2 on Lys93, followed by tripartite motif-containing protein 21 (TRIM21)-mediated ubiquitination through K63-linkage and degradation in the lysosome. The findings reveal a new role for SUCLG2 in mitochondrial dysfunction and clarify the mechanism of the succinylation-mediated protein homeostasis of SUCLG2 in LUAD, thus providing a theoretical basis for developing anti-cancer drugs targeting SUCLG2.

更新日期：2023-10-30

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