Dynamic Dystroglycan Complexes Mediate Cell Entry of Lassa Virus

ABSTRACT Recognition of functional receptors by viruses is a key determinant for their host range, tissue tropism, and disease potential. The highly pathogenic Lassa virus (LASV) currently represents one of the most important emerging pathogens. The major cellular receptor for LASV in human cells is...

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Autores principales:	Antonio Herrador, Chiara Fedeli, Emilia Radulovic, Kevin P. Campbell, Hector Moreno, Gisa Gerold, Stefan Kunz
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	arenavirus proteomics tropism viral entry virus receptor Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/0e5cae2956054cb5a743f7c4d33df33a
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spelling	oai:doaj.org-article:0e5cae2956054cb5a743f7c4d33df33a2021-11-15T15:55:26ZDynamic Dystroglycan Complexes Mediate Cell Entry of Lassa Virus10.1128/mBio.02869-182150-7511https://doaj.org/article/0e5cae2956054cb5a743f7c4d33df33a2019-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02869-18https://doaj.org/toc/2150-7511ABSTRACT Recognition of functional receptors by viruses is a key determinant for their host range, tissue tropism, and disease potential. The highly pathogenic Lassa virus (LASV) currently represents one of the most important emerging pathogens. The major cellular receptor for LASV in human cells is the ubiquitously expressed and evolutionary highly conserved extracellular matrix receptor dystroglycan (DG). In the host, DG interacts with many cellular proteins in a tissue-specific manner. The resulting distinct supramolecular complexes likely represent the functional units for viral entry, and preexisting protein-protein interactions may critically influence DG’s function in productive viral entry. Using an unbiased shotgun proteomic approach, we define the largely unknown molecular composition of DG complexes present in highly susceptible epithelial cells that represent important targets for LASV during viral transmission. We further show that the specific composition of cellular DG complexes can affect DG’s function in receptor-mediated endocytosis of the virus. Under steady-state conditions, epithelial DG complexes underwent rapid turnover via an endocytic pathway that shared some characteristics with DG-mediated LASV entry. However, compared to steady-state uptake of DG, LASV entry via DG occurred faster and critically depended on additional signaling by receptor tyrosine kinases and the downstream effector p21-activating kinase. In sum, we show that the specific molecular composition of DG complexes in susceptible cells is a determinant for productive virus entry and that the pathogen can manipulate the existing DG-linked endocytic pathway. This highlights another level of complexity of virus-receptor interaction and provides possible cellular targets for therapeutic antiviral intervention. IMPORTANCE 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.Antonio HerradorChiara FedeliEmilia RadulovicKevin P. CampbellHector MorenoGisa GeroldStefan KunzAmerican Society for Microbiologyarticlearenavirusproteomicstropismviral entryvirus receptorMicrobiologyQR1-502ENmBio, Vol 10, Iss 2 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	arenavirus proteomics tropism viral entry virus receptor Microbiology QR1-502
spellingShingle	arenavirus proteomics tropism viral entry virus receptor Microbiology QR1-502 Antonio Herrador Chiara Fedeli Emilia Radulovic Kevin P. Campbell Hector Moreno Gisa Gerold Stefan Kunz Dynamic Dystroglycan Complexes Mediate Cell Entry of Lassa Virus
description	ABSTRACT Recognition of functional receptors by viruses is a key determinant for their host range, tissue tropism, and disease potential. The highly pathogenic Lassa virus (LASV) currently represents one of the most important emerging pathogens. The major cellular receptor for LASV in human cells is the ubiquitously expressed and evolutionary highly conserved extracellular matrix receptor dystroglycan (DG). In the host, DG interacts with many cellular proteins in a tissue-specific manner. The resulting distinct supramolecular complexes likely represent the functional units for viral entry, and preexisting protein-protein interactions may critically influence DG’s function in productive viral entry. Using an unbiased shotgun proteomic approach, we define the largely unknown molecular composition of DG complexes present in highly susceptible epithelial cells that represent important targets for LASV during viral transmission. We further show that the specific composition of cellular DG complexes can affect DG’s function in receptor-mediated endocytosis of the virus. Under steady-state conditions, epithelial DG complexes underwent rapid turnover via an endocytic pathway that shared some characteristics with DG-mediated LASV entry. However, compared to steady-state uptake of DG, LASV entry via DG occurred faster and critically depended on additional signaling by receptor tyrosine kinases and the downstream effector p21-activating kinase. In sum, we show that the specific molecular composition of DG complexes in susceptible cells is a determinant for productive virus entry and that the pathogen can manipulate the existing DG-linked endocytic pathway. This highlights another level of complexity of virus-receptor interaction and provides possible cellular targets for therapeutic antiviral intervention. IMPORTANCE 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.
format	article
author	Antonio Herrador Chiara Fedeli Emilia Radulovic Kevin P. Campbell Hector Moreno Gisa Gerold Stefan Kunz
author_facet	Antonio Herrador Chiara Fedeli Emilia Radulovic Kevin P. Campbell Hector Moreno Gisa Gerold Stefan Kunz
author_sort	Antonio Herrador
title	Dynamic Dystroglycan Complexes Mediate Cell Entry of Lassa Virus
title_short	Dynamic Dystroglycan Complexes Mediate Cell Entry of Lassa Virus
title_full	Dynamic Dystroglycan Complexes Mediate Cell Entry of Lassa Virus
title_fullStr	Dynamic Dystroglycan Complexes Mediate Cell Entry of Lassa Virus
title_full_unstemmed	Dynamic Dystroglycan Complexes Mediate Cell Entry of Lassa Virus
title_sort	dynamic dystroglycan complexes mediate cell entry of lassa virus
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/0e5cae2956054cb5a743f7c4d33df33a
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_version_	1718427134406426624

Dynamic Dystroglycan Complexes Mediate Cell Entry of Lassa Virus

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