Simple epithelium keratins 8 and 18 provide resistance to Fas-mediated apoptosis. The protection occurs through a receptor-targeting modulation

doi:10.1083/jcb.200102130

Published 20 August 2001. doi:10.1083/jcb.200102130

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© The Rockefeller University Press, 0021-9525/2001/8/763 $5.00
The Journal of Cell Biology, Volume 154, Number 4, August 20, 2001 763-774

Article

Simple epithelium keratins 8 and 18 provide resistance to Fas-mediated apoptosis. The protection occurs through a receptor-targeting modulation

Stéphane Gilbert¹^,2, Anne Loranger², Nathalie Daigle² and Normand Marceau¹^,2

¹ Centre de recherche en cancérologie et Département de médecine, Université Laval, Québec, Canada, G1K 7P4
² Centre de recherche de L'Hôtel-Dieu de Quebec (CHUQ), Québec, Canada, G1R 2J6

Address correspondence to Normand Marceau, Centre de recherche HDQ (CHUQ), 9 McMahon, Québec, Canada, G1R 2J6. Tel.: (418) 691-5559. Fax: (418) 691-5439. E-mail: normand.marceau{at}crhdq.ulaval.ca

Keratins 8 and 18 belong to the keratin family of intermediatefilament (IF) proteins and constitute a hallmark for all simpleepithelia, including the liver. Hepatocyte IFs are made solelyof keratins 8 and 18 (K8/K18). In these cells, the loss of onepartner via a targeted null mutation in the germline resultsin hepatocytes lacking K8/K18 IFs, thus providing a model ofchoice for examining the function(s) of simple epithelium keratins.Here, we report that K8-null mouse hepatocytes in primary cultureand in vivo are three- to fourfold more sensitive than wild-type(WT) mouse hepatocytes to Fas-mediated apoptosis after stimulationwith Jo2, an agonistic antibody of Fas ligand. This increasedsensitivity is associated with a higher and more rapid caspase-3activation and DNA fragmentation. In contrast, no differencein apoptosis is observed between cultured K8-null and WT hepatocytesafter addition of the Fas-related death-factors tumor necrosisfactor (TNF) ${alpha}$ or TNF-related apoptosis-inducing ligand. Analysesof the Fas distribution in K8-null and WT hepatocytes in cultureand in situ demonstrate a more prominent targeting of the receptorto the surface membrane of K8-null hepatocytes. Moreover, alteringFas trafficking by disrupting microtubules with colchicine reducesby twofold the protection generated against Jo2-induced lethalaction in K8-null versus WT hepatocytes. Together, the resultsstrongly suggest that simple epithelium K8/K18 provide resistanceto Fas-mediated apoptosis and that this protection occurs througha modulation of Fas targeting to the cell surface.

Key Words: keratin; Fas; Golgi; microtubules; hepatocyte

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