期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：30
DOI：10.1073/pnas.2123065119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
The continued rapid evolution of SARS-CoV-2 and the emergence of immune-evading variants pose significant challenges to COVID-19 prevention and control, highlighting the urgent need for development of novel antiviral therapies. Our study found that SARS-CoV-2 infection promotes host succinylation and inhibits several key enzymes of the TCA, a crucial metabolic pathway that connects carbohydrate, fat, and protein metabolism, as well as regulating cellular energy. Additionally, viral NSP14 is capable to participate in succinylation through interacting with host SIRT5, a cellular desuccinylase. It is noteworthy that succinylation inhibitors can significantly reduce the viral replication, as a potential guide for the treatment of COVID-19.
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.
