A disease-and phosphorylation-related nonmechanical function for keratin 8

NO Ku, MB Omary - The Journal of cell biology, 2006 - rupress.org
NO Ku, MB Omary
The Journal of cell biology, 2006rupress.org
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 …
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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