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J Biol Chem. 2017 Oct 6;292(40):16527-16538. doi: 10.1074/jbc.M117.802090. Epub 2017 Aug 23.

Leucine-rich repeat-containing G protein-coupled receptor 4 facilitates vesicular stomatitis virus infection by binding vesicular stomatitis virus glycoprotein.

Author information

1
From the Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
2
the Department of Molecular and Cellular Medicine, Institute of Biosciences and Technology, Texas A&M University Health Sciences Center, Houston, Texas 77030.
3
the CIRI, Centre International de Recherche en Infectiologie, Lyon F69364, France.
4
the INSERM, U1111, 46 Allée d'Italie, Lyon, F69364, France.
5
the Ecole Normale Supérieure de Lyon, 46 Allée d'Italie, Lyon F69364, France.
6
the CNRS, UMR5308, 46 Allée d'Italie, Lyon F69364, France.
7
the University of Lyon, Lyon I, UMS3444/US8 BioSciences Gerland, Lyon F69364, France.
8
the Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China, and.
9
Shanghai Bioray Laboratories Inc., Shanghai 200241, China.
10
From the Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China, myliu@bio.ecnu.edu.cn.
11
From the Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China, bdu.ecnu@gmail.com.

Abstract

Vesicular stomatitis virus (VSV) and rabies and Chandipura viruses belong to the Rhabdovirus family. VSV is a common laboratory virus to study viral evolution and host immune responses to viral infection, and recombinant VSV-based vectors have been widely used for viral oncolysis, vaccination, and gene therapy. Although the tropism of VSV is broad, and its envelope glycoprotein G is often used for pseudotyping other viruses, the host cellular components involved in VSV infection remain unclear. Here, we demonstrate that the host protein leucine-rich repeat-containing G protein-coupled receptor 4 (Lgr4) is essential for VSV and VSV-G pseudotyped lentivirus (VSVG-LV) to infect susceptible cells. Accordingly, Lgr4-deficient mice had dramatically decreased VSV levels in the olfactory bulb. Furthermore, Lgr4 knockdown in RAW 264.7 cells also significantly suppressed VSV infection, and Lgr4 overexpression in RAW 264.7 cells enhanced VSV infection. Interestingly, only VSV infection relied on Lgr4, whereas infections with Newcastle disease virus, influenza A virus (A/WSN/33), and herpes simplex virus were unaffected by Lgr4 status. Of note, assays of virus entry, cell ELISA, immunoprecipitation, and surface plasmon resonance indicated that VSV bound susceptible cells via the Lgr4 extracellular domain. Pretreating cells with an Lgr4 antibody, soluble LGR4 extracellular domain, or R-spondin 1 blocked VSV infection by competitively inhibiting VSV binding to Lgr4. Taken together, the identification of Lgr4 as a VSV-specific host factor provides important insights into understanding VSV entry and its pathogenesis and lays the foundation for VSV-based gene therapy and viral oncolytic therapeutics.

KEYWORDS:

G protein-coupled receptor (GPCR); Lgr4; Pseudotyped virus; VSV; cell sorting; gene knockout; immunohistochemistry; surface plasmon resonance (SPR); virus entry

PMID:
28842478
PMCID:
PMC5633117
DOI:
10.1074/jbc.M117.802090
[Indexed for MEDLINE]
Free PMC Article

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