CVB3 VP1 interacts with MAT1 to inhibit cell proliferation by interfering with Cdk-activating kinase complex activity in CVB3-induced acute pancreatitis

Coxsackievirus B3 (CVB3) belongs to the genus Enterovirus of family Picornaviridae and can cause acute acinar pancreatitis in adults. However, molecular mechanisms pathogenesis underlying CVB3-induced have remained unclear. In this study, we discovered that CVB3 capsid protein VP1 inhibited pancreatic cell proliferation exerted strong cytopathic effects on HPAC cells. Through yeast two-hybrid, co-immunoprecipitation, confocal microscopy, show Menage a trois 1 (MAT1), subunit Cdk-Activating Kinase (CAK) complex involved transcription, is novel interaction with VP1. Moreover, MAT1 accumulation localization, thus interfering its CDK7. Furthermore, could suppress CAK enzymic phosphorylation activity towards RNA Pol II CDK4/6, direct substrates CAK. also suppresses retinoblastoma (pRb), an indirect substrate, especially at phospho-pRb Ser 780 807/811 residues, which are associated proliferation. Finally, present evidence using deletion mutants C-terminal domain (VP1-D8, 768-859aa) minimal region required for MAT1, furthermore, VP1-D8 alone was sufficient arrest cells G1/S phase as observed during infection. Taken together, demonstrate inhibit assembly through block MAT1-mediated CAK-CDK4/6-Rb signaling, ultimately These findings substantially extend our basic understanding CVB3-mediated pancreatitis, providing candidates strategic therapeutic targeting.