The global succinylation of SARS-CoV-2–infected host cells reveals drug targets

Author:

Liu Quan1234ORCID,Wang Heming5,Zhang He3,Sui Liyan2,Li Letian3,Xu Wang3,Du Shouwen6ORCID,Hao Pengfei3,Jiang Yuhang3,Chen Jing3,Qu Xiaoyun7,Tian Mingyao3ORCID,Zhao Yinghua2,Guo Xuerui8,Wang Xingye9,Song Wu9ORCID,Song Guangqi510ORCID,Wei Zhengkai4ORCID,Hou Zhijun11,Wang Guoqing12,Sun Minhua1ORCID,Li Xiao3,Lu Huijun3,Zhuang Xinyu3,Jin Ningyi3,Zhao Yicheng29ORCID,Li Chang3,Liao Ming1713

Affiliation:

1. 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

2. 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

3. Research Unit of Key Technologies for Prevention and Control of Virus Zoonoses, Chinese Academy of Medical Sciences, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, 130122 China

4. School of Life Sciences and Engineering, Foshan University, 528011 Foshan, China

5. Department of Gastroenterology, Zhongshan Hospital, Fudan University, 200437 Shanghai, China

6. Department of Infectious Diseases, The Second Clinical Medical College (Shenzhen People’s Hospital) of Jinan University, 518020 Shenzhen, China

7. Key Laboratory of Zoonosis of Ministry of Agriculture and Rural Affairs, South China Agricultural University, 510642 Guangzhou, China

8. School of Pharmacy, Jilin University, 130012 Changchun, China

9. Clinical Medical College, Changchun University of Chinese Medicine, 130117 Changchun, China

10. Shanghai Institute of Liver Diseases, 200032 Shanghai, China

11. College of Wildlife and Protected Area, Northeast Forestry University, 150040 Harbin, China

12. Department of Pathogenbiology, College of Basic Medicine, Jilin University, 130012 Changchun, China

13. Maoming Branch, Guangdong Laboratory for Lingnan Modern Agriculture, 525000 Maoming, China

Abstract

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.

Funder

National Natural Science Foundation of China

CAMS Innovation fund fo Medical Sciences

National Key Lab of Proteomics

Pearl River Talent Plan in Guangdong Province

Scientific and Technological Research Projects of Foshan

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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