Mapping of the Lassa virus LAMP1 binding site reveals unique determinants not shared by other old world arenaviruses.

Hadar Israeli,Ron Diskin,Anastasiya Shulman,Hadas Cohen-Dvashi,Amir Shimon,Sean P.J Whelan

doi:10.1371/journal.ppat.1006337

Abstract

Cell entry of many enveloped viruses occurs by engagement with cellular receptors, followed by internalization into endocytic compartments and pH-induced membrane fusion. A previously unnoticed step of receptor switching was found to be critical during cell entry of two devastating human pathogens: Ebola and Lassa viruses. Our recent studies revealed the functional role of receptor switching to LAMP1 for triggering membrane fusion by Lassa virus and showed the involvement of conserved histidines in this switching, suggesting that other viruses from this family may also switch to LAMP1. However, when we investigated viruses that are genetically close to Lassa virus, we discovered that they cannot bind LAMP1. A crystal structure of the receptor-binding module from Morogoro virus revealed structural differences that allowed mapping of the LAMP1 binding site to a unique set of Lassa residues not shared by other viruses in its family, illustrating a key difference in the cell-entry mechanism of Lassa virus that may contribute to its pathogenicity.

Highlights

Receptor switching is a newly discovered event in the cell entry process of Lassa virus (LASV) [1], a zoonotic, enveloped, negative-strand RNA virus that belongs to the Arenaviridae family [2]
We used a structure-guided approach to investigate whether other Arenaviridae utilize LAMP1 for cell entry
We previously showed that a triad of histidines on GP1 is important for binding LAMP1 [13], and we further demonstrated that the binding of LAMP1 triggers the spike of LASV to catalyze membrane fusion by potentiating its response to pH [14]

Summary

Introduction

Receptor switching is a newly discovered event in the cell entry process of Lassa virus (LASV) [1], a zoonotic, enveloped, negative-strand RNA virus that belongs to the Arenaviridae family [2]. Through a process of macropinocytosis [6, 7], LASV is internalized and reaches a late endosomal compartment. In this acidifying environment, LASV changes its binding specificity and engages LAMP1, a ubiquitous protein of lysosomes and late endosomes [1]. A requirement for receptor switching has been identified for Ebola virus, which binds to the Neimann-Pick C1 protein in the lysosome to infect cells [8, 9]. Receptor switching is an emerging theme for viral entry that may be relevant for other viruses as well

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Conclusion