Tight junction protein LSR is a host defense factor against SARS-CoV-2 infection in the small intestine

被引：1

作者：

An, Yanan ^{[1
,2
,3
]}

Wang, Chao ^{[4
,5
]}

Wang, Ziqi ^{[1
,2
,3
]}

Kong, Feng ^{[6
,7
]}

Liu, Hao ^{[1
,2
,3
]}

Jiang, Min ^{[8
]}

Liu, Ti ^{[9
]}

Zhang, Shu ^{[9
]}

Du, Kaige ^{[9
]}

Yin, Liang ^{[6
,7
]}

Jiao, Peng ^{[5
,10
]}

Li, Ying ^{[1
,2
,3
]}

Fan, Baozhen ^{[11
]}

Zhou, Chengjun ^{[12
]}

Wang, Mingxia ^{[1
,2
,3
]}

Sun, Hui ^{[1
,2
,3
]}

Lei, Jie ^{[9
]}

Zhao, Shengtian ^{[5
,6
,10
]}

Gong, Yongfeng ^{[1
,2
,3
]}

机构：

[1] Binzhou Med Univ, Dept Physiol, Yantai, Shandong, Peoples R China

[2] Shandong Engn Res Ctr Mol Med Renal Dis, Yantai, Shandong, Peoples R China

[3] Binzhou Med Univ, Lab Tight Junct, Yantai, Shandong, Peoples R China

[4] Shandong Univ, Hosp 2, Cheeloo Coll Med, Dept Urol, Jinan, Shandong, Peoples R China

[5] Shandong Univ, Qilu Hosp, Cheeloo Coll Med, Dept Urol, Jinan, Shandong, Peoples R China

[6] Shandong Prov Engn Lab Urol Tissue Reconstruct, Jinan, Shandong, Peoples R China

[7] Shandong First Med Univ, Dept Cent Lab, Shandong Prov Hosp, Jinan, Shandong, Peoples R China

[8] Binzhou Med Univ, Dept Pharmacol, Yantai, Shandong, Peoples R China

[9] Shandong Prov Ctr Dis Control & Prevent, Jinan, Shandong, Peoples R China

[10] Binzhou Med Univ Hosp, Dept Urol, Binzhou, Shandong, Peoples R China

[11] Binzhou Med Univ, Dept Urol, Yantai Affiliated Hosp, Yantai, Shandong, Peoples R China

[12] Shandong Univ, Hosp 2, Cheeloo Coll Med, Dept Pathol, Jinan, Shandong, Peoples R China

来源：

EMBO JOURNAL | 2024年 / 43卷 / 23期

基金：

中国国家自然科学基金;

关键词：

ACE2; Antiviral; Host Factor; LSR; SARS-CoV-2; STIMULATED LIPOPROTEIN RECEPTOR; BLOOD-PRESSURE; GENE-EXPRESSION; OVEREXPRESSION; PALMITOYLATION; IDENTIFICATION; HYPERLIPIDEMIA; RESPONSES; TARGET;

D O I：

10.1038/s44318-024-00281-4

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The identification of host factors with antiviral potential is important for developing effective prevention and therapeutic strategies against SARS-CoV-2 infection. Here, by using immortalized cell lines, intestinal organoids, ex vivo intestinal tissues and humanized ACE2 mouse model as proof-of-principle systems, we have identified lipolysis-stimulated lipoprotein receptor (LSR) as a crucial host defense factor against SARS-CoV-2 infection in the small intestine. Loss of endogenous LSR enhances ACE2-dependent infection by SARS-CoV-2 Spike (S) protein-pseudotyped virus and authentic SARS-CoV-2 virus, and exogenous administration of LSR protects against viral infection. Mechanistically, LSR interacts with ACE2 both in cis and in trans, preventing its binding to S protein, and thus inhibiting viral entry and S protein-mediated cell-cell fusion. Finally, a small LSR-derived peptide blocks S protein binding to the ACE2 receptor in vitro. These results identify both a previously unknown function for LSR in antiviral host defense against SARS-CoV-2, with potential implications for peptide-based pan-variant therapeutic interventions. Host cell factors that affect the interaction of SARS-CoV-2 Spike (S) protein with its receptor ACE2 can modulate SARS-CoV-2 infection. This study shows that lipolysis-stimulated lipoprotein receptor (LSR) acts as a defense factor against SARS-CoV-2 by impairing S protein binding to ACE2.LSR suppresses SARS-CoV-2 infection in the small intestine.LSR blocks viral entry and restricts S protein-mediated cell-cell fusion.LSR interacts with ACE2 both in and in , preventing its binding to S protein. Lipolysis-stimulated lipoprotein receptor (LSR) and its peptide derivative inhibit SARS-CoV-2 entry into host cells by blocking interaction between viral Spike protein and its ACE2 receptor.

引用

页码：6124 / 6151

页数：28

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