Int J Biol Sci 2022; 18(12):4744-4755. doi:10.7150/ijbs.73057 This issue

Research Paper

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

Bingpeng Yan1*, Shuofeng Yuan1*, Jianli Cao1*, Kingchun Fung1, Pok-Man Lai1, Feifei Yin2,3,4,5, Kong-Hung Sze1,6, Zhenzhi Qin1, Yubin Xie1, Zi-Wei Ye1, Terrence Tsz-Tai Yuen1, Kenn Ka-Heng Chik1,6, Jessica Oi-Ling Tsang1,6, Zijiao Zou1, Chris Chun-Yiu Chan1, Cuiting Luo1, Jian-Piao Cai1, Kwok-Hung Chan1,6, Tom Wai-Hing Chung7, Anthony Raymond Tam8, Hin Chu1,6,9, Dong-Yan Jin6,10,11, Ivan Fan-Ngai Hung8,9, Kwok-Yung Yuen1,3,4,6,7,9,11, Richard Yi-Tsun Kao1,6, Jasper Fuk-Woo Chan1,3,4,6,7,9,11,✉

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

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Abstract

Graphic 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