Epiplakin deficiency aggravates murine caerulein-induced acute pancreatitis and favors the formation of acinar keratin granules.

Karl L Wögenstein,Pavel Strnad,Mariia Lunova,Sandra Szabo,Martin Wagner,Peter Fuchs,Peter Boor,Johannes Haybaeck,Gerhard Wiche,Zoltan Rakonczay

doi:10.1371/journal.pone.0108323

Abstract

Epiplakin, a member of the plakin protein family, is exclusively expressed in epithelial tissues and was shown to bind to keratins. Epiplakin-deficient (EPPK−/−) mice showed no obvious spontaneous phenotype, however, EPPK−/− keratinocytes displayed faster keratin network breakdown in response to stress. The role of epiplakin in pancreas, a tissue with abundant keratin expression, was not yet known. We analyzed epiplakin’s expression in healthy and inflamed pancreatic tissue and compared wild-type and EPPK−/− mice during caerulein-induced acute pancreatitis. We found that epiplakin was expressed primarily in ductal cells of the pancreas and colocalized with apicolateral keratin bundles in murine pancreatic acinar cells. Epiplakin’s diffuse subcellular localization in keratin filament-free acini of K8-deficient mice indicated that its filament-associated localization in acinar cells completely depends on its binding partner keratin. During acute pancreatitis, epiplakin was upregulated in acinar cells and its redistribution closely paralleled keratin reorganization. EPPK−/− mice suffered from aggravated pancreatitis but showed no obvious regeneration phenotype. At the most severe stage of the disease, EPPK−/− acinar cells displayed more keratin aggregates than those of wild-type mice. Our data propose epiplakin to be a protective protein during acute pancreatitis, and that its loss causes impaired disease-associated keratin reorganization.

Highlights

Epiplakin, a large 725 kDa protein encoded by a single exon, was originally isolated as an autoantigen from a patient suffering from subepidermal blistering [1,2]
Epiplakin is expressed in ductal and acinar cells of the exocrine pancreas and its subcellular localization depends on keratin filaments
Besides its strong expression in ductal cells, epiplakin was expressed in acinar cells where it almost always colocalized with K8-positive apicolateral filaments (Fig. 1B, C, D)

Summary

Introduction

A large 725 kDa protein encoded by a single exon, was originally isolated as an autoantigen from a patient suffering from subepidermal blistering [1,2]. Mice lacking acinar keratins did not show increased susceptibility to experimentally induced pancreatitis [14]. In preliminary experiments we found that in response to caerulein-induced pancreatitis increased epiplakin expression paralleled that of keratin. These findings suggest a potential role of epiplakin in pancreatic injury. To address this question, we analyzed the pancreatic expression pattern of epiplakin in more detail and compared the susceptibility of wild-type and EPPK2/2 mice to caerulein-induced acute pancreatitis and their pancreatic acinar keratin filament network organization

Methods

Results

Conclusion