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

作　　者：Jiao Guo Yi Wan Yang Liu Xiaoying Jia Siqi Dong Gengfu Xiao Wei Wang 

机构地区：[1]State Key Laboratory of Virology,Wuhan Institute of Virology,Center for Biosafety Mega-Science,Chinese Academy of Sciences,Wuhan 430071,China [2]University of the Chinese Academy of Sciences,Beijing 100049,China [3]The Xi'an Key Laboratory of Pathogenic Microorganism and Tumor Immunity,School of Basic Medicine,Xi'an Medical University,Xi'an 710021,China

出　　处：《Virologica Sinica》2024年第4期600-608,共9页中国病毒学（英文版）

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

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.

关 键 词：Lassa virus(LASV) Lysosome-associated membrane protein 1 (LAMP1) GLYCOPROTEIN Receptor switch Membrane fusion 

分 类 号：R373[医药卫生—病原生物学]