Old World arenavirus infection interferes with the expression of functional alpha-dystroglycan in the host cell.
alpha-Dystroglycan (alpha-DG) is an important cellular receptor for extracellular matrix (ECM) proteins as well as the Old World arenaviruses lymphocytic choriomeningitis virus (LCMV) and the human pathogenic Lassa fever virus (LFV). Specific O-glycosylation of alpha-DG is critical for its function as receptor for ECM proteins and arenaviruses. Here, we investigated the impact of arenavirus infection on alpha-DG expression. Infection with an immunosuppressive LCMV isolate caused a marked reduction in expression of functional alpha-DG without affecting biosynthesis of DG core protein or global cell surface glycoprotein expression. The effect was caused by the viral glycoprotein (GP), and it critically depended on alpha-DG binding affinity and GP maturation. An equivalent effect was observed with LFVGP. Viral GP was found to associate with a complex between DG and the glycosyltransferase LARGE in the Golgi. Overexpression of LARGE restored functional alpha-DG expression in infected cells. We provide evidence that virus-induced down-modulation of functional alpha-DG perturbs DG-mediated assembly of laminin at the cell surface, affecting normal cell-matrix interactions.
Rojek
Jillian M
JM
Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, CA 92037, USA.
Campbell
Kevin P
KP
Oldstone
Michael B A
MB
Kunz
Stefan
S
D000818:Animals; D018049:Arenaviruses, Old World / Q000502:physiology*; D002460:Cell Line; D002522:Chlorocebus aethiops; D049030:Dystroglycans / Q000378:metabolism*; D005786:Gene Expression Regulation; D006031:Glycosylation; D016695:Glycosyltransferases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007797:Laminin / Q000378:metabolism; D051379:Mice; D011485:Protein Binding; D014158:Transcription, Genetic / Q000235:genetics; D014764:Viral Proteins / Q000378:metabolism
D007797:Laminin; D014764:Viral Proteins; D049030:Dystroglycans; D016695:Glycosyltransferases