Cdk5rap3 as a modulator of the UFMylation pathway is indispensable for survival and function of pancreatic acinar cells

Abstract

Abstract The acinus is the functional unit of the exocrine pancreas that produces and secretes a large amount of digestive enzymes. Damage and dysfunction of pancreatic acinar cells (PACs) may lead to malnutrition, pancreatitis and other pathological conditions. To cope with the high demand of protein synthesis and secretion, PACs possess an extensive network of rough endoplasmic reticulum (RER) where proteins are translated, modified and transported to Golgi apparatus for further modifications and packaging into zymogen granules (ZGs). The UFM1 (Ubiquitin fold modifier 1) conjugation system has been reported to clear up jammed nascent proteins on the ER membrane and maintain the ER homeostasis. Cdk5rap3 is one of the key components of the UFM1 system and its physiological function and working mechanism is currently under active investigation. We investigated its role in pancreatic homeostasis of protein synthesis using a PAC-specific knockout mouse model. We found that ablation of Cdk5rap3 in PACs led to fewer ZGs, loss of RER, acinar to ductal metaplasia (ADM) and degeneration of the acini compartment. Then, we further tested if it is involved in co-translational quality control of ER proteins. Interestingly, we found that the protein level of the ribosomal stalling reporter was much higher in Cdk5rap3 knockout cells, suggesting that Cdk5rap3 is a part of the quality control mechanism of ER proteins. Furthermore, we found that the reduced level of Cdkrap3 was correlated with human pancreatic diseases. Together, our results strongly suggest that Cdk5rap3 is essential for the survival and function of pancreatic acinar cells.