Cell entry of Lassa virus induces tyrosine phosphorylation of dystroglycan

Abstract

Summary: The extracellular matrix (ECM) receptor dystroglycan (DG) serves as a cellular receptor for the highly pathogenic arenavirus Lassa virus (LASV) that causes a haemorrhagic fever with high mortality in human. In the host cell, DG provides a molecular link between the ECM and the actin cytoskeleton via the adapter proteins utrophin or dystrophin. Here we investigated post-translational modifications of DG in the context of LASV cell entry. Using the tyrosine kinase inhibitor genistein, we found that tyrosine kinases are required for efficient internalization of virus particles, but not virus-receptor binding. Engagement of cellular DG by LASV envelope glycoprotein (LASV GP) in human epithelial cells induced tyrosine phosphorylation of the cytoplasmic domain of DG. LASV GP binding to DG further resulted in dissociation of the adapter protein utrophin from virus-bound DG. This virus-induced dissociation of utrophin was affected by genistein treatment, suggesting a role of receptor tyrosine phosphorylation in the process. Virus binding to cellular receptors frequently induces signaling that serves as a "knock on the door" to prime the host cell for subsequent steps of viral entry. Here, we found that binding of the highly pathogenic Lassa virus to its cellular receptor dystroglycan induces signaling, resulting in tyrosine phosphorylation of the cytoplasmic domain of the receptor. These signaling events are accompanied by the dissociation of dystroglycan from the cytoskeletal adaptor protein utrophin, likely facilitating internalization of the virus-receptor complex. © 2012 Blackwell Publishing Ltd.