Keratins 8 and 18 (K8 and K18) are heteropolymeric intermediate filament phosphoglycoproteins of simple-type epithelia. Mutations in K8 and K18 predispose the affected individual to liver disease as they protect hepatocytes from apoptosis. K18 undergoes dynamic O-linked N-acetylglucosamine glycosylation at Ser 30, 31 and 49. We investigated the function of K18 glycosylation by generating mice that overexpress human K18 S30/31/49A substitution mutants that cannot be glycosylated (K18-Gly g-), and compared the susceptibility of these mice to injury with wild-type and other keratin-mutant mice. K18-Gly g- mice are more susceptible to liver and pancreatic injury and apoptosis induced by streptozotocin or to liver injury by combined N-acetyl-D-glucosaminidase inhibition and Fas administration. The enhanced apoptosis in the livers of mice that express K18-Gly- involves the inactivation of Akt1 and protein kinase Cø as a result of their site-specific hypophosphorylation. Akt1 binds to K8, which probably contributes to the reciprocal hyperglycosylation and hypophosphorylation of Akt1 that occurs on K18 hypoglycosylation, and leads to decreased Akt1 kinase activity. Therefore, K18 glycosylation provides a unique protective role in epithelial injury by promoting the phosphorylation and activation of cell-survival kinases.
Bibliographical noteFunding Information:
We are grateful to R. Oshima (The Sanford-Burnham Medical Research Institute) and T. Magin (University of Leipzig) for making the mice that express wild-type K18 and the K18-null available to us, Y. Chen-Tsai and the Stanford University Transgenic Facility for helping generate the transgenic mice, E. Resurreccion for assistance with immune staining and P. Chu for assistance with hematoxylin and eosin staining. This work was supported by NIH grant DK47918 and the Department of Veterans Affairs (M.B.O.), NIH Digestive Disease Center grant DK56339 to Stanford University, NIH Michigan Gastrointestinal Peptide Research Center grant DK34933 and WCU project (R31-2008-000-10086-0) from the Korean Ministry of Education, Science and Technology to N. -O.K.
All Science Journal Classification (ASJC) codes
- Cell Biology