Abstract
Aim:
To investigate the detailed mechanism of Japanese encephalitis virus (JEV) cell entry.
Materials & methods:
Utilize a siRNA library targeting cellular membrane trafficking genes to identify key molecules that mediate JEV entry into human neuronal cells.
Results:
JEV enters human neuronal cells by caveolin-1-mediated endocytosis, which depends on a two-step regulation of actin cytoskeleton remodeling triggered by RhoA and Rac1: RhoA activation promoted the phosphorylation of caveolin-1, and then Rac1 activation facilitated caveolin-associated viral internalization. Specifically, virus attachment activates the EGFR-PI3K signaling pathway, thereby leading to RhoA activation.
Conclusion:
This work provides a detailed picture of the entry route and intricate cellular events following the entry of JEV into human neuronal cells, and promotes a better understanding of JEV entry.
Keywords:
Caveolin-1; EGFR; Japanese encephalitis virus; actin regulation; endocytosis; neuronal cells.
MeSH terms
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Actin Cytoskeleton / drug effects
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Actin Cytoskeleton / metabolism*
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Actin Cytoskeleton / virology*
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Actin Depolymerizing Factors / metabolism
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Actin Depolymerizing Factors / pharmacology
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Animals
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Caveolin 1 / drug effects
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Caveolin 1 / genetics
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Caveolin 1 / metabolism*
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Cell Line
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Cell Membrane / chemistry
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Cell Membrane / metabolism
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Cell Membrane / virology
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Cholesterol / metabolism
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Cricetinae
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Dynamin II / genetics
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Dynamin II / metabolism
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Encephalitis Virus, Japanese / genetics
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Encephalitis Virus, Japanese / metabolism*
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Encephalitis Virus, Japanese / pathogenicity
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Encephalitis Virus, Japanese / physiology*
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Encephalitis, Japanese / virology
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Endocytosis / physiology
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ErbB Receptors / metabolism
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HEK293 Cells
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Host-Pathogen Interactions / physiology
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Humans
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Life Cycle Stages / physiology
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Membrane Transport Proteins / genetics
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Membrane Transport Proteins / metabolism
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Neurons / virology
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation
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Protein-Tyrosine Kinases / metabolism
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Protein-Tyrosine Kinases / pharmacology
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RNA, Small Interfering / genetics
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Signal Transduction
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Transfection
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Virus Attachment
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Virus Internalization / drug effects*
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rac1 GTP-Binding Protein / metabolism
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rac1 GTP-Binding Protein / pharmacology
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rhoA GTP-Binding Protein / metabolism
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rhoA GTP-Binding Protein / pharmacology
Substances
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Actin Depolymerizing Factors
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CAV1 protein, human
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Caveolin 1
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Membrane Transport Proteins
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RAC1 protein, human
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RNA, Small Interfering
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RHOA protein, human
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Cholesterol
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Phosphatidylinositol 3-Kinases
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EGFR protein, human
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ErbB Receptors
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Protein-Tyrosine Kinases
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rac1 GTP-Binding Protein
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rhoA GTP-Binding Protein
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Dynamin II