Molecular analysis of the interaction of LCMV with its cellular receptor [alpha]-dystroglycan.
alpha-Dystroglycan (DG) has been identified as the cellular receptor for lymphocytic choriomeningitis virus (LCMV) and Lassa fever virus (LFV). This subunit of DG is a highly versatile cell surface molecule that provides a molecular link between the extracellular matrix (ECM) and a beta-DG transmembrane component, which interacts with the actin-based cytoskeleton. In addition, DG exhibits a complex pattern of interaction with a wide variety of ECM and cellular proteins. In the present study, we characterized the binding of LCMV to alpha-DG and addressed the role of alpha-DG-associated host-derived proteins in virus infection. We found that the COOH-terminal region of alpha-DG's first globular domain and the NH2-terminal region of the mucin-related structures of alpha-DG together form the binding site for LCMV. The virus-alpha-DG binding unlike ECM alpha-DG interactions was not dependent on divalent cations. Despite such differences in binding, LCMV and laminin-1 use, in part, an overlapping binding site on alpha-DG, and the ability of an LCMV isolate to compete with laminin-1 for receptor binding is determined by its binding affinity to alpha-DG. This competition of the virus with ECM molecules for receptor binding likely explains the recently found correlation between the affinity of LCMV binding to alpha-DG, tissue tropism, and pathological potential. LCMV strains and variants with high binding affinity to alpha-DG but not low affinity binders are able to infect CD11c+ dendritic cells, which express alpha-DG at their surface. Infection followed by dysfunction of these antigen-presenting cells contributes to immunosuppression and persistent viral infection in vivo.
Kunz
S
S
The Scripps Research Institute, Division of Virology, Department of Neuropharmacology, La Jolla, CA 92037, USA.
Sevilla
N
N
McGavern
D B
DB
Campbell
K P
KP
Oldstone
M B
MB
D000818:Animals; D001117:Arenaviridae Infections / Q000378:metabolism / Q000821:virology; D001665:Binding Sites; D001667:Binding, Competitive; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000378:metabolism*; D049030:Dystroglycans; D016326:Extracellular Matrix Proteins / Q000737:chemistry / Q000378:metabolism; D005260:Female; D007797:Laminin / Q000378:metabolism; D008217:Lymphocytic choriomeningitis virus / Q000302:isolation & purification / Q000378:metabolism* / Q000472:pathogenicity*; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D017434:Protein Structure, Tertiary; D013154:Spleen / Q000378:metabolism / Q000821:virology
D003598:Cytoskeletal Proteins; D016326:Extracellular Matrix Proteins; D007797:Laminin; D008562:Membrane Glycoproteins; C121346:laminin 1; D049030:Dystroglycans