Cathepsin B hyperactivation facilitates exosome release of CVB3 particles and exacerbation of acute pancreatitis by impairing lysosomal integrity and acidification.

Abstract

UNLABELLED: Lysosomal cathepsin B (CTSB) exhibits diverse roles in physiological and pathological processes. Upregulation and trypsinogen-activating function of CTSB have been reported in experimental secretagogue-elicited AP. Whether CTSB regulates the lysosome pathway and viral release in viral acute pancreatitis (AP) remains obscure. In a murine model of Coxsackievirus 3 (CVB3)-induced AP, we tested effects of CTSB on lysosome integrity and exosome secretion. CVB3 infection does- and time-dependently upregulates expression and activity of CTSB, the most elevated CTS in pancreas, and induces lysosomal instability and extra-lysosomal translocation of CTSB. Overexpression of CTSB increases viral replication. Inhibition of CTSB with CA074Me reduces virion release via rescuing lysosome integrity and acidity. Mechanically, CTSB hyperactivation and inappropriate cytoplasmic translocation increase viral infections by decreasing LAMP-1 + lysosomes, exacerbating lysosomal membrane permeabilization (LMP), and enhancing exosomal release of virions. Pharmaceutical inhibition of CTSB improves AP pathology via reducing viral infection. Our study reveals a critical role of hyperactivated CTSB in disrupting lysosome integrity, facilitating exosomal release of CVB3 particles and exacerbation of pancreas pathology in AP. These findings offer new insights into the pathogenesis of viral AP and suggest that CTSB and exosome are potential therapeutic targets for viral AP. IMPORTANCE: This study uncovers a critical role of lysosome cathepsin B (CTSB) in exacerbating viral acute pancreatitis (AP). CVB3 infection of acinar cells induces lysosomal membrane permeability and CTSB cytosolic translocation. Hyperactivated CTSB increases viral infections by decreasing lysosomes, exacerbating LMP, and enhancing exosomal release of virions. Pharmaceutical inhibition of CTSB protects mice against viral dissemination and AP pathology, suggesting that CTSB and exosome are potential therapeutic targets for viral AP.