Antibody-induced internalisation of retroviral envelope glycoproteins is a signal initiation event.

George Kassiotis,George R Young,Jan Attig,Veera Panova,Jonathan P Stoye

doi:10.1371/journal.ppat.1008605

George Kassiotis, George R Young + Show 3 more

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https://doi.org/10.1371/journal.ppat.1008605

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Abstract

As obligate parasites, viruses highjack, modify and repurpose the cellular machinery for their own replication. Viral proteins have, therefore, evolved biological functions, such as signalling potential, that alter host cell physiology in ways that are still incompletely understood. Retroviral envelope glycoproteins interact with several host proteins, extracellularly with their cellular receptor and anti-envelope antibodies, and intracellularly with proteins of the cytoskeleton or sorting, endocytosis and recirculation pathways. Here, we examined the impact of endogenous retroviral envelope glycoprotein expression and interaction with host proteins, particularly antibodies, on the cell, independently of retroviral infection. We found that in the commonly used C57BL/6 substrains of mice, where murine leukaemia virus (MLV) envelope glycoproteins are expressed by several endogenous MLV proviruses, the highest expressed MLV envelope glycoprotein is under the control of an immune-responsive cellular promoter, thus linking MLV envelope glycoprotein expression with immune activation. We further showed that antibody ligation induces extensive internalisation from the plasma membrane into endocytic compartments of MLV envelope glycoproteins, which are not normally subject to constitutive endocytosis. Importantly, antibody binding and internalisation of MLV envelope glycoproteins initiates signalling cascades in envelope-expressing murine lymphocytic cell lines, leading to cellular activation. Similar effects were observed by MLV envelope glycoprotein ligation by its cellular receptor mCAT-1, and by overexpression in human lymphocytic cells, where it required an intact tyrosine-based YXXΦ motif in the envelope glycoprotein cytoplasmic tail. Together, these results suggest that signalling potential is a general property of retroviral envelope glycoproteins and, therefore, a target for intervention.

Highlights

The outcome of viral infection depends on the balance between host defences and virus’ ability to counteract, avoid or exploit them [1, 2]
We found that in the commonly used C57BL/6 substrains of mice, where murine leukaemia virus (MLV) envelope glycoproteins are expressed by several endogenous MLV proviruses, the highest expressed MLV envelope glycoprotein is under the control of an immune-responsive cellular promoter, linking MLV envelope glycoprotein expression with immune activation
Using murine leukaemia viruses as models of infectious and endogenous retroviruses, we show that antibody binding to retroviral envelopes induces extensive internalisation of the envelope-antibody complex and initiates signalling cascades, leading to transcriptional activation of envelope glycoproteinexpressing lymphocytes

Summary

Introduction

The outcome of viral infection depends on the balance between host defences and virus’ ability to counteract, avoid or exploit them [1, 2]. The envelopes of exogenous infectious retroviruses are not the only ones targeted by the host antibody response. Both the human and mouse genomes contain several endogenous retroviral env genes that have retained the potential to express full-length envelopes [9,10,11,12,13,14,15]. Antibodies to murine endogenous retroviral envelopes can be spontaneously induced in healthy mice with age and have been linked with disease severity in SLE mouse models [25, 26]

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