GPR143 directs virus-induced cell vacuolation via the MKK6–p38 pathway

Cytoplasmic vacuolization is observed in vertebrate cells following exposure to viral pathogens. Causing cytoplasmic vacuolization is a key step for many viruses to induce cell death, however, the mechanisms underlying cytoplasmic vacuolization are unclear. Nervous necrosis virus (NNV) induces pronounced cytoplasmic vacuoles in the brain during infection. G protein-coupled receptors (GPCRs) regulate autophagosomes and cause vacuolation. Here, we used grouper and red-spotted grouper NNV (RGNNV) as the model to investigate the role of GPCRs in mediating virus induced cellular vacuolation in the central nervous system. GPR143 enhanced RGNNV-induced cytoplasmic vacuolation through intracellular binding to the RGNNV capsid protein and influenced the binding of autophagosomes and lysosomes. RGNNV enhanced interactions between GPR143 and MKK6, which phosphorylated p38 mitogen-activated protein kinase, subsequently activating the mTOR pathway, augmenting the binding of autophagosomes and lysosomes, and causing cytoplasmic vacuolation. Our study adds a new pathway by which viruses cause vacuolation in vertebrates.