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J. Cell Biol. 155 (3): 415-426

Copyright © 2001 by the Rockefeller University Press.


Keratin attenuates tumor necrosis factor–induced cytotoxicity through association with TRADD

Hiroyasu Inada1, Ichiro Izawa1, Miwako Nishizawa1, Eriko Fujita4, Tohru Kiyono2, Toshitada Takahashi3, Takashi Momoi4, and Masaki Inagaki1

1 Division of Biochemistry, Aichi Cancer Center Research Institute, Aichi 464-8681, Japan
2 Division of Virology, Aichi Cancer Center Research Institute, Aichi 464-8681, Japan
3 Division of Immunology, Aichi Cancer Center Research Institute, Aichi 464-8681, Japan
4 Division of Development and Differentiation, National Institute of Neuroscience, NCNP, Tokyo 187-8502, Japan

Address correspondence to Dr. Masaki Inagaki, Division of Biochemistry, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusaku, Nagoya, Aichi 464-8681, Japan. Tel.: 81-52-762-6111 (ext. 7020). Fax: 81-52-763-5233. E-mail: minagaki{at}

Abstract: Keratin 8 and 18 (K8/18) are the major components of intermediate filament (IF) proteins of simple or single-layered epithelia. Recent data show that normal and malignant epithelial cells deficient in K8/18 are nearly 100 times more sensitive to tumor necrosis factor (TNF)–induced cell death. We have now identified human TNF receptor type 1 (TNFR1)–associated death domain protein (TRADD) to be the K18-interacting protein. Among IF proteins tested in two-hybrid systems, TRADD specifically bound K18 and K14, type I (acidic) keratins. The COOH-terminal region of TRADD interacted with the coil Ia of the rod domain of K18. Endogenous TRADD coimmunoprecipitated with K18, and colocalized with K8/18 filaments in human mammary epithelial cells. Overexpression of the NH2 terminus (amino acids 1–270) of K18 containing the TRADD-binding domain as well as overexpression of K8/18 in SW13 cells, which are devoid of keratins, rendered the cells more resistant to killing by TNF. We also showed that overexpressed NH2 termini of K18 and K8/18 were associated with endogenous TRADD in SW13 cells, resulting in the inhibition of caspase-8 activation. These results indicate that K18 may sequester TRADD to attenuate interactions between TRADD and activated TNFR1 and moderate TNF-induced apoptosis in simple epithelial cells.

Key Words: apoptosis; keratin 8; keratin 18; TNF; TRADD

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