Intermediate Filament Keratins in The Exocrine Pancreas

Intermediate filament keratins are cytoskeletal components in epithelial tissues, including the exocrine pancreas. Keratin (K) intermediate filaments are highly conserved proteins that are expressed from early developmental stages up to the differentiated epithelial cells in adult individuals. A multitude of specific cellular functions have been identified for keratins expressed in simple epithelia, such as the pancreas, liver, lung and intestine. These functions vary, depending on the cell- and tissue type, as well as the developmental stage and changes in the cellular environment. Keratins are composed of dynamic, post-translationally regulated cytoplasmic filaments built up of obligate heteropolymers of type I and a type II keratins. In simple epithelia, the main keratins are type II K8 and K7, and type I K18, K19 and K20.

The simple epithelium of the exocrine pancreas is responsible for the secretion of digestive enzymes into the duodenum. The exocrine pancreas comprises more than 85% of the pancreatic mass and consists of acinar and ductal cells. The acinar cells express mainly K8 and K18, which assemble into both cytoplasmic and apicolateral filaments, as well as minor levels of K19 and K20, which are confined to the apicolateral regions under basal conditions. Pancreatic duct cells express mainly K19 (type I) and K7 (type II).

Pancreatic keratins respond quickly to cell stress by keratin phosphorylation and filament breakdown followed by keratin upregulation, de novo filament formation and remodeling during the recovery phase in experimental exocrine pancreatic injury models. However, despite these dynamic stress responses, mutations or genetic deletion of K8 and K18 in humans or mouse models, only have modest effects on exocrine pancreatic health and stress tolerance. This is different from other simple epithelial tissues – most notably the liver – where K8, K18 and K19 mutations or deletions cause clear pathological outcomes. In contrast, overexpression of K8/K18 leads to pathological outcomes in the exocrine pancreas but not in the liver. These seemingly antagonistic outcomes in two cell types that have similar keratin expression patterns, underscores the versatile and tissue-specific function of keratins. The biological reasons underlying the different susceptibility of the exocrine acinar cells to keratin deficiencies, compared to other simple epithelial cells is not fully understood, but may, in part, be due to the increased levels of Regeneration protein-II observed in the pancreas in several K8/K18 deficient mouse models.