Dynamic Dystroglycan Complexes Mediate Cell Entry of Lassa Virus

Author:

Herrador Antonio12,Fedeli Chiara12,Radulovic Emilia12,Campbell Kevin P.34567,Moreno Hector12,Gerold Gisa8910,Kunz Stefan12ORCID

Affiliation:

1. Institute of Microbiology, Lausanne University Hospital, Lausanne, Switzerland

2. University of Lausanne, Lausanne, Switzerland

3. Howard Hughes Medical Institute, Iowa City, Iowa, USA

4. Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, The University of Iowa, Iowa City, Iowa, USA

5. Department of Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA

6. Department of Neurology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA

7. Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA

8. TWINCORE - Center for Experimental and Clinical Infection Research, Institute for Experimental Virology, Hannover, Germany

9. Department of Clinical Microbiology, Umeå University, Umeå, Sweden

10. Wallenberg Centre for Molecular Medicine (WCMM), Umeå University, Umeå, Sweden

Abstract

Recognition of cellular receptors allows emerging viruses to break species barriers and is an important determinant for their disease potential. Many virus receptors have complex tissue-specific interactomes, and preexisting protein-protein interactions may influence their function. Combining shotgun proteomics with a biochemical approach, we characterize the molecular composition of the functional receptor complexes used by the highly pathogenic Lassa virus (LASV) to invade susceptible human cells. We show that the specific composition of the receptor complexes affects productive entry of the virus, providing proof-of-concept. In uninfected cells, these functional receptor complexes undergo dynamic turnover involving an endocytic pathway that shares some characteristics with viral entry. However, steady-state receptor uptake and virus endocytosis critically differ in kinetics and underlying signaling, indicating that the pathogen can manipulate the receptor complex according to its needs. Our study highlights a remarkable complexity of LASV-receptor interaction and identifies possible targets for therapeutic antiviral intervention.

Funder

Paul D. Wellstone Muscular Dystrophy Cooperative Research Center

Deutsche Forschungsgemeinschaft

Human Frontier Science Program

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung

Publisher

American Society for Microbiology

Subject

Virology,Microbiology

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