Cdk5rap3-mediated regulation of lysosomal and ER membrane proteins is pivotal for the survival and function of pancreatic acinar cells

The acinus is the functional unit of the exocrine pancreas that produces and secretes a large quantity of digestive enzymes. Damage and dysfunction of pancreatic acinar cells (PACs) may lead to malnutrition, pancreatitis, and other pathological conditions. CDK5 regulatory subunit-associated protein 3 (Cdk5rap3), a multifunctional protein, is essential for animal development and normal physiology of multiple organs and tissues. Interestingly, the recent studies suggest its involvement in endoplasmic reticulum (ER)-phagy, a lysosomal degradation of the subdomains of the endoplasmic reticulum (ER). Herein, we attempted to investigate its physiological function in pancreatic acinar cells. We found that Cdk5rap3-deficient PACs contained fewer zymogen granules and underwent acinar-to-ductal metaplasia (ADM) and apoptosis, thereby resulting in a significant loss of acinar compartment. Interestingly, Cdk5rap3 ablation led to the increase of lysosomal hydrolase cathepsin B and lysosome-associated membrane protein 1 (LAMP1), indicating its novel function in the regulation of lysosomal homeostasis and activity. Elevated cathepsin B activity may lead to aberrant activation of trypsinogen and apoptosis of Cdk5rap3-deficient acinar cells, whereas the increase of lysosomal proteins may enhance lysosomal activity that in turn promotes ADM. Furthermore, Cdk5rap3 knockout led to substantial changes in the rough ER structure and a significant increase in selective ER membrane proteins, including cytoskeleton-linking membrane protein 63 (CLIMP63). Our results from both mouse tissues and tissue culture cells strongly suggest that Cdk5rap3 plays a pivotal role in regulating homeostasis of the lysosome and the ER that is essential for the survival and physiological function of pancreatic acinar cells.