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

IF 5.5 3区 医学 Q1 Medicine Virologica Sinica Pub Date : 2024-08-01 DOI:10.1016/j.virs.2024.06.001
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Abstract

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.

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鉴定拉沙病毒糖蛋白 1 中参与受体转换的残基。
拉沙病毒(LASV)是一种导致拉沙出血热的有包膜负义 RNA 病毒。拉沙病毒的成功侵入需要病毒糖蛋白 1(GP1)进行受体转换,从其主要受体α-软骨糖(α-DG)转换到其内体受体溶酶体相关膜蛋白 1(LAMP1)。据报道,LASV GP1 中的一个保守组氨酸三元组是受体切换的原因。为了验证其他非保守残基也有助于受体切换的假设,我们构建了一系列突变的 LASV GP1 蛋白,并测试了它们与 LAMP1 的结合情况。结果发现,L84、K88、L107 和 H170 这四个残基对受体切换至关重要。用相应的淋巴细胞色素膜炎病毒(LCMV)残基(L84N、K88E、L10F 和 H170S)代替这四个残基中的任何一个,都会降低 LASV GP1 与 LAMP1 的结合亲和力。此外,在 pH 值为 4.5 和 5.2 时,所有突变都会导致糖蛋白前体(GPC)介导的膜融合降低。带有 GPCL84N 或 GPCK88E 的伪型病毒在多种细胞类型中的感染性急剧下降,而 L107F 和 H170S 对感染性只有轻微影响。通过生物层光干涉测定法,我们发现所有四种突变体与 LAMP1 的结合亲和力都下降了,其结合亲和力顺序为 L84N > L107F > K88E > H170S。本研究首次发现的四个氨基酸位点对深入研究LASV受体转换和免疫逃逸的发生机制以及开发后备抗LASV感染药物具有重要的参考意义。
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来源期刊
Virologica Sinica
Virologica Sinica Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
7.70
自引率
1.80%
发文量
3149
期刊介绍: Virologica Sinica is an international journal which aims at presenting the cutting-edge research on viruses all over the world. The journal publishes peer-reviewed original research articles, reviews, and letters to the editor, to encompass the latest developments in all branches of virology, including research on animal, plant and microbe viruses. The journal welcomes articles on virus discovery and characterization, viral epidemiology, viral pathogenesis, virus-host interaction, vaccine development, antiviral agents and therapies, and virus related bio-techniques. Virologica Sinica, the official journal of Chinese Society for Microbiology, will serve as a platform for the communication and exchange of academic information and ideas in an international context. Electronic ISSN: 1995-820X; Print ISSN: 1674-0769
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