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Translocation of TRAF proteins regulates apoptotic threshold of cells
R H Arch1, R W Gedrich, C B Thompson
1Gwen Knapp Center for Lupus and Immunology Research, Howard Hughes Medical Institute, Department of Medicine, University of Chicago, IL 60637, USA. rarch@im.wustl.edu
Abstract:
Tumor necrosis factor (TNF) receptor-associated factors (TRAFs) are involved in signaling pathways triggered by members of the TNF receptor (TNFR) family and other cell surface proteins. After recruitment to a receptor, TRAFs initiate formation of multiprotein complexes that induce downstream events, such as translocation of transcription factor nuclear factor kappaB (NF-kappaB) and activation of c-Jun N-terminal kinase (JNK). Several proteins in these complexes play important roles in regulation of apoptosis. However, the fate of TRAF-containing complexes once assembled in response to receptor multimerization is not understood. In this report, we demonstrate that crosslinking of TNFR family members or interaction of TRAF2 with the cytoplasmic protein A20 leads to intracellular translocation of TRAF2. This redistribution leads to depletion of the cytoplasmic pool of TRAF2. The ratio between soluble and insoluble TRAF2 determines the sensitivity of cells to TNF-alpha-induced apoptosis and may play an important role in limiting further TRAF-dependent signal transduction.
Insights
Tumor necrosis factor (TNF) receptor-associated factors (TRAFs) redistribute within cells upon receptor activation. This TRAF2 translocation impacts cellular apoptosis sensitivity and signal transduction.
Area of Science:
- Cellular signaling pathways
- Molecular biology
- Immunology
Background:
- Tumor necrosis factor (TNF) receptor-associated factors (TRAFs) mediate signaling from TNF receptor (TNFR) family members.
- TRAFs assemble into multiprotein complexes that regulate transcription factor nuclear factor kappaB (NF-kappaB) and c-Jun N-terminal kinase (JNK) activation.
- The role of TRAF complex dynamics in apoptosis regulation remains unclear.
Purpose of the Study:
- To investigate the intracellular fate of TRAF-containing complexes after receptor activation.
- To determine how TRAF2 redistribution affects cellular responses to TNF-alpha.
- To elucidate the mechanisms regulating TRAF-dependent signal transduction.
Main Methods:
- Stimulation of TNFR family members and TRAF2 interaction with A20.
- Analysis of TRAF2 intracellular localization and pool dynamics.
- Assessment of cellular sensitivity to TNF-alpha-induced apoptosis.
Main Results:
- Crosslinking of TNFRs or A20 interaction with TRAF2 induces TRAF2 translocation.
- This redistribution depletes the cytoplasmic pool of TRAF2.
- The ratio of soluble to insoluble TRAF2 correlates with TNF-alpha-induced apoptosis sensitivity.
Conclusions:
- TRAF2 intracellular translocation is a key event following receptor activation.
- TRAF2 pool dynamics regulate cellular apoptosis sensitivity.
- TRAF redistribution may limit sustained TRAF-dependent signaling.