Caspase-cleaved TRAF1 negatively regulates the antiapoptotic signals of TRAF2 during TNF-induced cell death.
Tumor necrosis factor (TNF) signaling leads to pleiotropic responses in a wide range of cell types, in part by activating antiapoptotic and proapoptotic pathways. Previous studies have suggested that TNF receptor-associated factor (TRAF) 2 can mediate crucial antiapoptotic signals during TNF stimulation. However, it is unclear how the antiapoptotic signals via TRAF2 in TNF-R1 signaling is regulated. Here we show that TRAF1 is cleaved by caspase-8 into two fragments during apoptosis induced by TNF. Overexpression of the C-terminal cleavage product, TRAF1-c, increased TNF-induced cell death of hybridoma T cells. Importantly, we demonstrate that the cleavage product of TRAF1 coimmunoprecipitates with TRAF2 that is released from the TNF-R1 complex in response to prolonged TNF treatment. These results indicate that caspase-dependent cleavage of TRAF1 generates TRAF1-c fragments that are able to bind TRAF2, and then sequester TRAF2 from the TNF-R1 complex, rendering cells, at least in part, sensitive to TNF.
Jang
H D
HD
Division of Molecular Life Science and Center for Cell Signalling Research, Ewha Womans University, Seoul, 120-750, Korea.
Chung
Y M
YM
Baik
J H
JH
Choi
Y G
YG
Park
I S
IS
Jung
Y K
YK
Lee
S Y
SY
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001665:Binding Sites; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects*; D002460:Cell Line; D004274:DNA, Recombinant; D004305:Dose-Response Relationship, Drug; D006801:Humans; D010957:Plasmids / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D004274:DNA, Recombinant; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; D020169:Caspases