Phosphatidic acid phosphatase 1 impairs SARS-CoV-2 replication by affecting the glycerophospholipid metabolism pathway
Bingpeng Yan, Shuofeng Yuan, Jianli Cao, Kingchun Fung, Pok-Man Lai, Feifei Yin, Kong‐Hung Sze, Zhenzhi Qin, Yubin Xie, Zi‐Wei Ye, Terrence Tsz‐Tai Yuen, Kenn Ka‐Heng Chik, Jessica Oi‐Ling Tsang, Zijiao Zou, Chris Chun-Yiu Chan, Cuiting Luo, Jian‐Piao Cai, Kwok‐Hung Chan, Tom Wai-Hing Chung, Anthony Raymond Tam, Hin Chu, Dong‐Yan Jin, Ivan Fan‐Ngai Hung, Kwok‐Yung Yuen, Richard Yi-Tsun Kao, Jasper Fuk‐Woo Chan
Abstract
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.