Editors' ChoiceLIVER DISEASE

Protected from Death by Phosphorylating Keratins

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Science's STKE  11 Jul 2006:
Vol. 2006, Issue 343, pp. tw229
DOI: 10.1126/stke.3432006tw229

Chronic liver disease has been associated with increased phosphorylation of hepatocyte keratins (K8 and K18). Keratins are intermediate filament proteins that contribute to the mechanical stability of epithelial cells. Ku and Omary report a nonmechanical function for K8 in protecting hepatocytes from inflammation-induced death using transgenic mice expressing the human K8 G61C mutant, which is prevalent among humans with cirrhosis and fibrosis of the liver. Mice expressing the K8 G61C mutant were more susceptible to lethal liver injury in response to activation of the Fas signaling pathway than were wild-type mice or mice expressing human K8. However, the livers of the mice expressing K8 G61C were not more susceptible to perfusion injury, suggesting that the hepatocytes were not more fragile due to lack of intermediate filaments. The livers of the K8 G61C mice exhibited less phosphorylation of Ser73 in response to Fas activation than did K8 from wild-type mice. Indeed, K8 G61C was not an effective substrate for in vitro phosphorylation at Ser73 by several stress-activated protein kinases (p38, JNK, p42). Analysis of transgenic mice expressing K8 S73A showed increased hepatocyte apoptosis in response to Fas activation, mimicking the response in the K8 G61C mice. Phosphorylation of other stress-activated protein kinase substrates was increased in the K8 G61C and K8 S73A mouse livers compared with wild-type mouse livers. Thus, K8 may serve as a phosphorylation sponge preventing apoptosis by competing with the proapoptotic substrates of stress-activated protein kinases.

N.-O. Ku, M. B. Omary, A disease- and phosphorylation-related nonmechanical function for keratin 8. J. Cell Biol. 174, 115-125 (2006). [Abstract] [Full Text]

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