Survival of the Filamentous

Abstract

Epithelial cells devoid of the intermediate filament proteins keratin 8 (K8) and keratin 18 (K18) are 100 times as sensitive to apoptosis induced by tumor necrosis factor (TNF) as cells expressing these keratins. Inada et al. show that the NH 2 termini of K8 and K18 interact with the TNF receptor 1-associated death domain protein (TRADD). This interaction was detected by yeast two-hybrid analysis, coprecipitation and colocalization of endogenous proteins, and glutathione S -transferase fusion protein pull-down assays. Expression of K8 and K18 or just the NH 2 terminus of K18 protected cells from TNF-induced apoptosis, but not from apoptosis triggered by other stimuli, such as DNA damage, microtubule destabilization, or DNA topoisomerase inhibition. Cells expressing both K8 and K18 required higher than physiological amounts of TNF to cause dissociation of TRADD from the intermediate filaments and to activate caspase-8. Thus, K8 and K18 appear to protect cells from TNF-induced cell death by sequestering TRADD away from the TNF receptor, which blocks initiation of the apoptotic signaling cascade. H. Inada, I. Izawa, M. Nishizawa, E. Fujita, T. Kiyono, T. Takahashi, T. Momoi, M. Inagaki, Keratin attenuates tumor necrosis factor-induced cytotoxicity through association with TRADD. J. Cell Biol. 155 , 415-425 (2001). [Abstract] [Full Text]