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.

中文翻译：

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SARS-CoV-2 感染宿主细胞的整体琥珀酰化揭示了药物靶点

SARS-CoV-2 是 COVID-19 大流行的病原体，它在不断进化，凸显了开发新型抗病毒疗法的迫切需求。在这里，我们展示了对 Caco-2 细胞中 SARS-CoV-2 感染的基于定量质谱的琥珀酰蛋白质组学分析，揭示了宿主和病毒蛋白上琥珀酰化的显着重塑。SARS-CoV-2 感染促进 TCA 中几种关键酶的琥珀酰化，从而抑制细胞代谢途径。我们证明宿主蛋白琥珀酰化受病毒非结构蛋白 (NSP14) 通过与 sirtuin 5 (SIRT5) 的相互作用进行调节；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着的抗病毒作用。我们还发现 SARS-CoV-2 核衣壳和膜蛋白进行了琥珀酰化修饰，这在 SARS-CoV-2 及其变体中是保守的。总的来说，我们的研究结果揭示了一种由 SARS-CoV-2 介导的宿主蛋白翻译后修饰和细胞通路的调节机制，可能成为针对 COVID-19 的抗病毒药物靶点。