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Published online 11 December 2000. doi:10.1083/jcb.151.6.1247
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© The Rockefeller University Press, 0021-9525/2000//1247 $5.00
The Journal of Cell Biology, Volume 151, Number 6, , 2000 1247-1256

Original Article

Necrotic Death Pathway in FAS Receptor Signaling



Hirotaka Matsumuraa, Yusuke Shimizua, Yoshiyuki Ohsawab, Atsuo Kawaharaa, Yasuo Uchiyamab, and Shigekazu Nagataa,c

a Department of Genetics, Osaka University Medical School, Osaka 565-0871, Japan
b Department of Cell Biology and Anatomy, Osaka University Medical School, Osaka 565-0871, Japan
c Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Osaka 565-0871, Japan
Osaka University Medical School, B-3, Department of Genetics, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.81-6-68-79-33-1981-6-68-79-33-10

nagata{at}genetic.med.osaka-u.ac.jp

A caspase 8–deficient subline (JB6) of human Jurkat cells can be killed by the oligomerization of Fas-associated protein with death domain (FADD). This cell death process is not accompanied by caspase activation, but by necrotic morphological changes. Here, we show that the death effector domain of FADD is responsible for the FADD-mediated necrotic pathway. This process was accompanied by a loss of mitochondrial transmembrane potential ({Delta}{Psi}m), but not by the release of cytochrome c from mitochondria. Pyrrolidine dithiocarbamate, a metal chelator and antioxidant, efficiently inhibited the FADD-induced reduction of {Delta}{Psi}m and necrotic cell death. When human Jurkat, or its transformants, expressing mouse Fas were treated with Fas ligand or anti–mouse Fas antibodies, the cells died, showing characteristics of apoptosis. A broad caspase inhibitor (z-VAD–fmk) blocked the apoptotic morphological changes and the release of cytochrome c. However, the cells still died, and this cell death process was accompanied by a strong reduction in {Delta}{Psi}m, as well as necrotic morphological changes. The presence of z-VAD–fmk and pyrrolidine dithiocarbamate together blocked cell death, suggesting that both apoptotic and necrotic pathways can be activated through the Fas death receptor.

Key Words: apoptosis • caspase • Fas • mitochondrial membrane potential • necrosis

© 2000 The Rockefeller University Press

A. Kawahara's present address is Laboratory of Molecular Genetics, National Institute of Child Health and Human Development, Building 6B, Room 420, NIH, Bethesda, MD 20892.

Abbreviations used in this paper: BHA, butylated hydroxyanisole; DD, death domain; DED, death effector domain; FADD, Fas-associated protein with death domain; FasL, Fas ligand; FKBP, FK506-binding protein; LZ-FasL, FasL tagged with a leucine-zipper motif; PDTC, pyrrolidine dithiocarbamate; TNF, tumor necrosis factor; z-VAD–fmk, carbobenzoyl-Val-Ala-Asp-fluoromethylketone; {Delta}{Psi}m, mitochondrial transmembrane potential.


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