Key Laboratory of Livestock Disease Prevention of Guangdong Province, Scientific Observation and Experiment Station of Veterinary Drugs and Diagnostic Techniques of Guangdong Province, Ministry of Agriculture and Rural Affairs, Institute of Animal Health, Guangdong Academy of Agricultural Sciences, 510610 Guangzhou, China.
Center for Infectious Diseases and Pathogen Biology, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, State Key Laboratory of Human-Animal Zoonotic infectious Diseases, The First Hospital of Jilin University, Changchun, 130021 China.
Proc Natl Acad Sci U S A. 2022 Jul 26;119(30):e2123065119. doi: 10.1073/pnas.2123065119. Epub 2022 Jul 12.
SARS-CoV-2, the causative agent of the COVID-19 pandemic, undergoes continuous evolution, highlighting an urgent need for development of novel antiviral therapies. Here we show a quantitative mass spectrometry-based succinylproteomics analysis of SARS-CoV-2 infection in Caco-2 cells, revealing dramatic reshape of succinylation on host and viral proteins. SARS-CoV-2 infection promotes succinylation of several key enzymes in the TCA, leading to inhibition of cellular metabolic pathways. We demonstrated that host protein succinylation is regulated by viral nonstructural protein (NSP14) through interaction with sirtuin 5 (SIRT5); overexpressed SIRT5 can effectively inhibit virus replication. We found succinylation inhibitors possess significant antiviral effects. We also found that SARS-CoV-2 nucleocapsid and membrane proteins underwent succinylation modification, which was conserved in SARS-CoV-2 and its variants. Collectively, our results uncover a regulatory mechanism of host protein posttranslational modification and cellular pathways mediated by SARS-CoV-2, which may become antiviral drug targets against COVID-19.
SARS-CoV-2 是 COVID-19 大流行的病原体，不断进化，突显开发新型抗病毒疗法的迫切需求。在这里，我们展示了一种基于定量质谱的 SARS-CoV-2 在 Caco-2 细胞感染中的琥珀酰化蛋白质组学分析，揭示了宿主和病毒蛋白琥珀酰化的剧烈重塑。SARS-CoV-2 感染促进 TCA 中的几种关键酶的琥珀酰化，导致细胞代谢途径的抑制。我们证明宿主蛋白琥珀酰化受病毒非结构蛋白 (NSP14) 通过与 SIRT5 相互作用来调节；过表达的 SIRT5 可以有效抑制病毒复制。我们发现琥珀酰化抑制剂具有显著的抗病毒作用。我们还发现 SARS-CoV-2 核衣壳和膜蛋白发生琥珀酰化修饰，这在 SARS-CoV-2 及其变体中是保守的。总之，我们的研究结果揭示了 SARS-CoV-2 介导的宿主蛋白翻译后修饰和细胞途径的调节机制，这可能成为针对 COVID-19 的抗病毒药物靶点。
