Journal
JOURNAL OF CELL BIOLOGY
Volume 174, Issue 1, Pages 115-125Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200602146
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Funding
- NIDDK NIH HHS [P30 DK056339, R01 DK047918, DK47918, DK56339] Funding Source: Medline
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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. lament proteins.
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