Abstract
TNFR1 associated death domain protein (TRADD) contains an N-terminal TRAF binding domain and a C-terminal death domain along with nuclear import and export sequences that cause shuttling between the cytoplasm and nucleus. The death domain of TRADD contains the nuclear import sequence and expression of the core death domain (nuclear TRADD) results in exclusive nuclear localization and activation of a distinct apoptotic pathway. Cytoplasmic TRADD activates apoptosis through Fas-associated death domain protein (FADD) and caspase-8 activation that was blocked by caspase inhibitors or dominant-negative FADD. These inhibitors did not inhibit death induced by nuclear TRADD, which could only be inhibited by combining caspase inhibitors and a serine protease inhibitor. The pathway activated by nuclear TRADD requires caspase-9 catalytic activity. However, apoptosis activating factor deficiency confers only partial protection from death. This pathway represents an alternate means by which TRADD can regulate cell death independently of FADD and caspase-8 that occurs from the nucleus rather than the cytoplasm.
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Abbreviations
- AEBSF:
-
(4-(2-Aminoethyl)benzenesulfonyl fluoride hydrochloride)
- APAF-1:
-
apoptosis activating factor I
- FADD:
-
Fas associated death domain protein
- FADD-DD:
-
dominant-negative FADD
- IAP:
-
inhibitor of apoptosis protein
- ICR-191:
-
6-Chloro-9[3-(2-chloroethylamino)propylamino]-2-methyoxyacridine
- MEFs:
-
mouse embryonic fibroblasts
- siRNA:
-
short interfering RNA
- PARP:
-
poly(ADP-ribose) polymerase
- Stat-1:
-
signal transducer and activator of transcription I
- TNFR:
-
TNF receptor
- TRADD:
-
TNFR1 associated death domain protein
- YFP:
-
yellow fluorescent protein
- zVAD.fmk:
-
N-Benzyloxcarbonyl-Val-Ala-Asp(o-Me) fluoromethyl ketone
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Acknowledgements
We thank Drs. T Mak, J Yuan, G Stark, G Salvesen, and Y Lazebnik for providing critical cells and constructs. This work was supported by NIH Grant NS46353 (AT).
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Bender, L., Morgan, M., Thomas, L. et al. The adaptor protein TRADD activates distinct mechanisms of apoptosis from the nucleus and the cytoplasm. Cell Death Differ 12, 473–481 (2005). https://doi.org/10.1038/sj.cdd.4401578
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DOI: https://doi.org/10.1038/sj.cdd.4401578
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