GPR143 directs virus-induced cell vacuolation via MKK6-p38 pathway in teleost

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Cytoplasmic vacuolization is a well-known morphological phenomenon observed in vertebrate cells after exposure to bacterial or viral pathogens. Studies on cytoplasmic vacuolization focused on its role in cell death and survival processes. However, little is known about the mechanism of cytoplasmic vacuolization formation. Nervous necrosis virus (NNV), a devastating and multispecies marine virus affecting multiple species, induces pronounced cytoplasmic vacuoles in brain during infection. G protein-coupled receptors (GPCRs) are critical in regulating autophagosomes and generating vacuolation. Here, we investigated the specific role of G protein-coupled receptor (GPR) 143 in mediating RGNNV-induced cellular vacuolation in the central nervous system of teleost. We observed that it enhanced red-spotted grouper NNV (RGNNV)-induced cytoplasmic vacuolation through intracellular binding to the RGNNV capsid protein. GPR143 significantly influenced the binding of autophagosomes and lysosomes. Further analysis revealed that RGNNV enhanced the interaction of GPR143 with MKK6, which phosphorylation of p38 mitogen-activated protein kinase. This phosphorylation subsequently activated the mTOR pathway, augmenting the binding of autophagosomes and lysosomes and resulting in cytoplasmic vacuolation. Finally, GPR143-mutant zebrafish demonstrated diminished brain vacuolation and reduced fry mortality. These findings suggest that RGNNV–GPR143 interaction activated the MKK6–p38–mTOR pathway, fostering autophagosome and lysosome binding that leads to cytoplasmic vacuolation. Targeting the GPR143-mediated pathway may provide a new therapeutic strategy for virus-induced cellular vacuolation.

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