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© The Rockefeller University Press, 0021-9525/1998//2023 $5.00
The Journal of Cell Biology, Volume 143, Number 7, , 1998 2023-2032

Regular Articles

Mutation of a Major Keratin Phosphorylation Site Predisposes to Hepatotoxic Injury in Transgenic Mice



Nam-On Ku*,||, Sara A. Michie{ddagger},||, Roy M. Soetikno*,||, Evelyn Z. Resurreccion{ddagger},||, Rosemary L. Broome§,||, and M. Bishr Omary*,||

* Department of Medicine, {ddagger} Department of Pathology, and § Department of Veterinary Medicine, Veterans Administration Palo Alto Health Care System, Palo Alto, CA 94304; and the || Digestive Disease Center, Stanford University School of Medicine, Palo Alto, California 94305

Simple epithelia express keratins 8 (K8) and 18 (K18) as their major intermediate filament (IF) proteins. One important physiologic function of K8/18 is to protect hepatocytes from drug-induced liver injury. Although the mechanism of this protection is unknown, marked K8/18 hyperphosphorylation occurs in association with a variety of cell stresses and during mitosis. This increase in keratin phosphorylation involves multiple sites including human K18 serine-(ser)52, which is a major K18 phosphorylation site. We studied the significance of keratin hyperphosphorylation and focused on K18 ser52 by generating transgenic mice that overexpress a human genomic K18 ser52-> ala mutant (S52A) and compared them with mice that overexpress, at similar levels, wild-type (WT) human K18. Abrogation of K18 ser52 phosphorylation did not affect filament organization after partial hepatectomy nor the ability of mouse livers to regenerate. However, exposure of S52A-expressing mice to the hepatotoxins, griseofulvin or microcystin, which are associated with K18 ser52 and other keratin phosphorylation changes, resulted in more dramatic hepatotoxicity as compared with WT K18-expressing mice. Our results demonstrate that K18 ser52 phosphorylation plays a physiologic role in protecting hepatocytes from stress-induced liver injury. Since hepatotoxins are associated with increased keratin phosphorylation at multiple sites, it is likely that unique sites aside from K18 ser52, and phosphorylation sites on other IF proteins, also participate in protection from cell stress.

Key Words: keratins • phosphorylation • intermediate filaments • transgenic mice • liver

Abbreviations used in this paper: Emp, Empigen BB; GF, griseofulvin; IF, intermediate filament(s); K, keratin; MLR, microcystin LR; pS, phospho-serine; PVDF, polyvinylidene difluoride; S52A, transgenic mice that overexpress ser52-> ala K18; TG2, transgenic mice that overexpress wild-type human K18; WT, wild-type.

We are very grateful to Robert Oshima (The Burnham Institute, La Jolla, CA) for the use of the TG2 mice and for providing anti-mouse K18 antibodies, Harald Herrmann (German Cancer Research Center, Heidelberg, Germany) and Manijeh Pasdar (Universitsy of Alberta, Alberta, Canada) for their generous gifts of antibodies, Kris Morrow for preparing the figures, Marta Raygoza for animal breeding and care, Ron Van Groningen for serum testing, Romola Breckenridge for assisting with manuscript preparation, and Steve Avolicino (Histo-Tec Laboratory, Hayward, CA) for performing the histology staining.

Address reprint requests to Nam-On Ku, Palo Alto VA Medical Center, 3801 Miranda Avenue, 154J, Palo Alto, CA 94304. Fax: (415) 852-3259.


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