A disease- and phosphorylation-related nonmechanical function for keratin 8.
Keratin 8 (K8) variants predispose to human liver injury via poorly understood mechanisms. We generated transgenic mice that overexpress the human disease-associated K8 Gly61-to-Cys (G61C) variant and showed that G61C predisposes to liver injury and apoptosis and dramatically inhibits K8 phosphorylation at serine 73 (S73) via stress-activated kinases. This led us to generate mice that overexpress K8 S73-to-Ala (S73A), which mimicked the susceptibility of K8 G61C mice to injury, thereby providing a molecular link between K8 phosphorylation and disease-associated mutation. Upon apoptotic stimulation, G61C and S73A hepatocytes have persistent and increased nonkeratin proapoptotic substrate phosphorylation by stress-activated kinases, compared with wild-type hepatocytes, in association with an inability to phosphorylate K8 S73. Our findings provide the first direct link between patient-related human keratin variants and liver disease predisposition. The highly abundant cytoskeletal protein K8, and possibly other keratins with the conserved S73-containing phosphoepitope, can protect tissue from injury by serving as a phosphate "sponge" for stress-activated kinases and thereby provide a novel nonmechanical function for intermediate filament proteins.
Ku
Nam-On
NO
Department of Medicine, Palo Alto VA Medical Center and Stanford University School of Medicine, Palo Alto, CA 94304, USA. namonku@stanford.edu
Omary
M Bishr
MB
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D056486:Chemical and Drug Induced Liver Injury; D004195:Disease Models, Animal; D053222:Fas Ligand Protein; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007381:Intermediate Filament Proteins / Q000378:metabolism / Q000502:physiology; D053533:Keratin-8; D007633:Keratins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D008107:Liver Diseases / Q000235:genetics* / Q000473:pathology; D008111:Liver Function Tests; D008387:Marine Toxins; D008562:Membrane Glycoproteins / Q000008:administration & dosage / Q000737:chemistry; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D052998:Microcystins; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D009154:Mutation; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000737:chemistry; D010766:Phosphorylation; D048069:Tumor Necrosis Factors / Q000008:administration & dosage / Q000737:chemistry
C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007381:Intermediate Filament Proteins; C426203:KRT8 protein, human; D053533:Keratin-8; D008387:Marine Toxins; D008562:Membrane Glycoproteins; D052998:Microcystins; D010456:Peptides, Cyclic; D048069:Tumor Necrosis Factors; D007633:Keratins; D020928:Mitogen-Activated Protein Kinases; C057862:cyanoginosin LR