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.
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3 July 2006
Article|
July 03 2006
A disease- and phosphorylation-related nonmechanical function for keratin 8
Nam-On Ku,
Nam-On Ku
Department of Medicine, Palo Alto VA Medical Center and Stanford University School of Medicine, Palo Alto, CA 94304
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M. Bishr Omary
M. Bishr Omary
Department of Medicine, Palo Alto VA Medical Center and Stanford University School of Medicine, Palo Alto, CA 94304
Search for other works by this author on:
Nam-On Ku
Department of Medicine, Palo Alto VA Medical Center and Stanford University School of Medicine, Palo Alto, CA 94304
M. Bishr Omary
Department of Medicine, Palo Alto VA Medical Center and Stanford University School of Medicine, Palo Alto, CA 94304
Correspondence to Nam-On Ku: [email protected]
Abbreviations used in this paper: Ab, antibody; CREB, cAMP response element binding protein; EBS, epidermolysis bullosa simplex; HSE, high salt extraction; IF, intermediate filament; K, keratin; MLR, microcystin-LR; SAPK, stress-activated protein kinase; WT, wild type.
Received:
February 24 2006
Accepted:
May 26 2006
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2006
J Cell Biol (2006) 174 (1): 115–125.
Article history
Received:
February 24 2006
Accepted:
May 26 2006
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Nam-On Ku, M. Bishr Omary; A disease- and phosphorylation-related nonmechanical function for keratin 8 . J Cell Biol 3 July 2006; 174 (1): 115–125. doi: https://doi.org/10.1083/jcb.200602146
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