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© The Rockefeller University Press, 0021-9525/2002/6/975 $5.00
The Journal of Cell Biology, Volume 157, Number 6, June 10, 2002 975-984

Nuclear and cytoplasmic shuttling of TRADD induces apoptosis via different mechanisms

¹ Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157
² Department of Human Genetics and Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021

Address correspondence to Andrew Thorburn, Wake Forest University School of Medicine, Department of Cancer Biology, Medical Center Boulevard, Winston-Salem, NC 27157. Tel.: (336) 716-7587. Fax: (336) 715-0255. E-mail: athorbur{at}wfubmc.edu

The adapter protein tumor necrosis factor receptor (TNFR)1–associated death domain (TRADD) plays an essential role in recruiting signaling molecules to the TNFRI receptor complex at the cell membrane. Here we show that TRADD contains a nuclear export and import sequence that allow shuttling between the nucleus and the cytoplasm. In the absence of export, TRADD is found within nuclear structures that are associated with promyelocytic leukemia protein (PML) nuclear bodies. In these structures, the TRADD death domain (TRADD-DD) can activate an apoptosis pathway that is mechanistically distinct from its action at the membrane-bound TNFR1 complex. Apoptosis by nuclear TRADD-DD is promyelocytic leukemia protein dependent, involves p53, and is inhibited by Bcl-xL but not by caspase inhibitors or dominant negative FADD (FADD-DN). Conversely, apoptosis induced by TRADD in the cytoplasm is resistant to Bcl-xL, but sensitive to caspase inhibitors and FADD-DN. These data indicate that nucleocytoplasmic shuttling of TRADD leads to the activation of distinct apoptosis mechanisms that connect the death receptor apparatus to nuclear events.

Key Words: apoptosis; TRADD; leptomycin B; PML; p53

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