Identification of residues in Lassa virus glycoprotein 1 involved in receptor switch

作     者：Guo J. Wan Y. Liu Y. Jia X. Dong S. Xiao G. Wang W. 

作者机构：State Key Laboratory of Virology Wuhan Institute of Virology Center for Biosafety Mega-Science Chinese Academy of Sciences Wuhan 430071 China The Xi'an Key Laboratory of Pathogenic Microorganism and Tumor Immunity School of Basic Medicine Xi'an Medical University Xi'an 710021 China University of the Chinese Academy of Sciences Beijing 100049 China 

出 版 物：《Virologica Sinica》 (中国病毒学（英文版）)

年 卷 期：2024年第39卷第4期

页      面：600-608页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：CAS Wuhan Institute of Virology Science and Technology Planning Project of Shaanxi Provincial Education Department, (22JK0545) Natural Science Basic Research Program of Shaanxi Province, (2024JC-YBQN-0922) Natural Science Basic Research Program of Shaanxi Province Open Research Fund Program of the State Key Laboratory of Virology of China, (2023JZZD-01) National Natural Science Foundation of China, NSFC, (82172273, 31670165) National Natural Science Foundation of China, NSFC National Key Research and Development Program of China, NKRDPC, (2023YFC2605504, 2022YFC2303300) National Key Research and Development Program of China, NKRDPC Health research project of Shaanxi Province, (2022D040) 

主　　题：Glycoprotein Lassa virus (LASV) Lysosome-associated membrane protein 1 (LAMP1) Membrane fusion Receptor switch 

摘      要：Lassa virus (LASV) is an enveloped, negative-sense RNA virus that causes Lassa hemorrhagic fever. Successful entry of LASV requires the viral glycoprotein 1 (GP1) to undergo a receptor switch from its primary receptor alpha-dystroglycan (α-DG) to its endosomal receptor lysosome-associated membrane protein 1 (LAMP1). A conserved histidine triad in LASV GP1 has been reported to be responsible for receptor switch. To test the hypothesis that other non-conserved residues also contribute to receptor switch, we constructed a series of mutant LASV GP1 proteins and tested them for binding to LAMP1. Four residues, L84, K88, L107, and H170, were identified as critical for receptor switch. Substituting any of the four residues with the corresponding lymphocytic choriomeningitis virus (LCMV) residue (L84 ​N, K88E, L10F, and H170S) reduced the binding affinity of LASV GP1 for LAMP1. Moreover, all mutations caused decreases in glycoprotein precursor (GPC)-mediated membrane fusion at both pH 4.5 and 5.2. The infectivity of pseudotyped viruses bearing either GPCL84N or GPCK88E decreased sharply in multiple cell types, while L107F and H170S had only mild effects on infectivity. Using biolayer light interferometry assay, we found that all four mutants had decreased binding affinity to LAMP1, in the order of binding affinity being L84 ​N ​ ​L107F ​ ​K88E ​ ​H170S. The four amino acid loci identified for the first time in this study have important reference significance for the in-depth investigation of the mechanism of receptor switching and immune escape of LASV occurrence and the development of reserve anti-LASV infection drugs. © 2024 The Authors