Phosphatidic acid phosphatase 1 impairs SARS-CoV-2 replication by affecting the glycerophospholipid metabolism pathway

Bingpeng Yan^1*, Shuofeng Yuan^1*, Jianli Cao^1*, Kingchun Fung¹, Pok-Man Lai¹, Feifei Yin^2,3,4,5, Kong-Hung Sze^1,6, Zhenzhi Qin¹, Yubin Xie¹, Zi-Wei Ye¹, Terrence Tsz-Tai Yuen¹, Kenn Ka-Heng Chik^1,6, Jessica Oi-Ling Tsang^1,6, Zijiao Zou¹, Chris Chun-Yiu Chan¹, Cuiting Luo¹, Jian-Piao Cai¹, Kwok-Hung Chan^1,6, Tom Wai-Hing Chung⁷, Anthony Raymond Tam⁸, Hin Chu^1,6,9, Dong-Yan Jin^6,10,11, Ivan Fan-Ngai Hung^8,9, Kwok-Yung Yuen^{1,3,4,6,7,9,11}, Richard Yi-Tsun Kao^1,6, Jasper Fuk-Woo Chan^{1,3,4,6,7,9,11,✉}

1. State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China.
2. Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Medical University, Haikou, Hainan, China.
3. Academician Workstation of Hainan Province, Hainan Medical University, Haikou, Hainan, China.
4. Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China.
5. Department of Pathogen Biology, Hainan Medical University, Haikou, Hainan, China.
6. Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Hong Kong Special Administrative Region, China.
7. Department of Microbiology, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, China.
8. Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China.
9. Department of Infectious Disease and Microbiology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.
10. School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China.
11. Guangzhou Laboratory, Guangdong Province, China.
^*These authors contributed equally to this work as co-first authors.

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Citation:
Yan B, Yuan S, Cao J, Fung K, Lai PM, Yin F, Sze KH, Qin Z, Xie Y, Ye ZW, Yuen TTT, Chik KKH, Tsang JOL, Zou Z, Chan CCY, Luo C, Cai JP, Chan KH, Chung TWH, Tam AR, Chu H, Jin DY, Hung IFN, Yuen KY, Kao RYT, Chan JFW. Phosphatidic acid phosphatase 1 impairs SARS-CoV-2 replication by affecting the glycerophospholipid metabolism pathway. Int J Biol Sci 2022; 18(12):4744-4755. doi:10.7150/ijbs.73057. Available from https://www.ijbs.com/v18p4744.htm

Abstract

Viruses exploit the host lipid metabolism machinery to achieve efficient replication. We herein characterize the lipids profile reprogramming in vitro and in vivo using liquid chromatography-mass spectrometry-based untargeted lipidomics. The lipidome of SARS-CoV-2-infected Caco-2 cells was markedly different from that of mock-infected samples, with most of the changes involving downregulation of ceramides. In COVID-19 patients' plasma samples, a total of 54 lipids belonging to 12 lipid classes that were significantly perturbed compared to non-infected control subjects' plasma samples were identified. Among these 12 lipid classes, ether-linked phosphatidylcholines, ether-linked phosphatidylethanolamines, phosphatidylcholines, and ceramides were the four most perturbed. Pathway analysis revealed that the glycerophospholipid, sphingolipid, and ether lipid metabolisms pathway were the most significantly perturbed host pathways. Phosphatidic acid phosphatases (PAP) were involved in all three pathways and PAP-1 deficiency significantly suppressed SARS-CoV-2 replication. siRNA knockdown of LPIN2 and LPIN3 resulted in significant reduction of SARS-CoV-2 load. In summary, these findings characterized the host lipidomic changes upon SARS-CoV-2 infection and identified PAP-1 as a potential target for intervention for COVID-19.

Keywords: COVID-19, lipidomics, phosphatidic acid phosphatases, SARS-CoV-2