부산대학교 도서관

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. Author summary: The outcome of viral infection depends on the balance between host immunity and the ability of the virus to avoid, evade or subvert it. The envelope glycoproteins of diverse viruses, including retroviruses, are displayed on the surface of virions and of infected cells and thus constitute the major target of the host antibody response. Antibody responses are elicited not only against infectious viruses we acquire during our life-history, but also against the numerous retroviral envelopes encoded by our genome and acquired during our species' life-history. In turn, viruses have evolved ways to reduce exposure of their envelope glycoproteins to the host immune system, including constitutive endocytosis or antibody-induced internalisation. 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, ultimately leading to transcriptional activation of envelope glycoprotein-expressing lymphocytes. We further show that expression of endogenous retroviral envelopes is coupled to physiological lymphocyte activation, integrating them with the immune response. These findings reveal an unexpected layer of interaction between the host antibody response and retroviral envelope glycoproteins, which could be considered immune receptors. [ABSTRACT FROM AUTHOR]