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Vol. 18, Issue 11, 4493-4507, November 2007

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Old World Arenavirus Infection Interferes with the Expression of Functional -Dystroglycan in the Host Cell

Jillian M. Rojek^*, Kevin P. Campbell, Michael B.A. Oldstone^*, and Stefan Kunz^*

*Viral Immunobiology Laboratory, Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, CA 92037; and Departments of Molecular Physiology and Biophysics, Neurology, and Internal Medicine, Howard Hughes Medical Institute, University of Iowa College of Medicine, Iowa City, IA 52242

Submitted April 25, 2007; Revised August 2, 2007; Accepted August 22, 2007
Monitoring Editor: Jean Schwarzbauer

-Dystroglycan (-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 -DG is critical for its function as receptor for ECM proteins and arenaviruses. Here, we investigated the impact of arenavirus infection on -DG expression. Infection with an immunosuppressive LCMV isolate caused a marked reduction in expression of functional -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 -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 -DG expression in infected cells. We provide evidence that virus-induced down-modulation of functional -DG perturbs DG-mediated assembly of laminin at the cell surface, affecting normal cell–matrix interactions.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Stefan Kunz (stefanku{at}scripps.edu).

Abbreviations used: DG, dystroglycan; ECM, extracellular matrix; LCMV, lymphocytic choriomeningitis virus; LFV, Lassa virus; MOI, multiplicity of infection.

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