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TRAF1: lord without a RING
1Burnham Institute, La Jolla, CA 92037, USA. jzapata@burnham.org
Abstract:
Tumor necrosis factor (TNF) receptor-associated factors (TRAFs) constitute a family of adaptor proteins that associate with the cytosolic tail of particular TNF-family receptors (TNFR) and regulate cytokine signaling by linking TNFRs with downstream protein kinases, ubiquitin ligases, and other effector proteins. A total of six members of this family (TRAF1-6) have been identified in mammals. TRAF1 is unique among TRAFs because it lacks a RING finger domain present in TRAF2-6 that has been shown to be required for TRAF2- and TRAF6-mediated activities. TRAF1 also has the most restricted expression among TRAFs, and is found almost exclusively in activated lymphocytes, dendritic cells, and certain epithelia. Recent evidence obtained from TRAF1(-/-) mice shows that TRAF1-deficient T cells are hyper-responsive to TNF-alpha, having increased T cell receptor (TCR)-dependent T cell proliferation rates in vitro. Also, these TRAF1(-/-) mice had increased sensitivity to TNF-alpha-induced skin necrosis in vivo. These results support a role for TRAF1 as a negative regulator of signaling by certain TNF-family receptors. This review summarizes current knowledge about TRAF1, focusing on the new information provided by these TRAF1-deficient mice. Also, the pros and cons of TRAFs as potential targets for drug discovery are discussed.
Insights
Tumor necrosis factor (TNF) receptor-associated factors (TRAFs) are adaptor proteins. TRAF1 acts as a negative regulator of TNF signaling, as shown by hyper-responsive T cells and increased skin necrosis in TRAF1-deficient mice.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Tumor necrosis factor (TNF) receptor-associated factors (TRAFs) are adaptor proteins crucial for cytokine signaling.
- Six TRAF family members (TRAF1-6) exist in mammals, mediating signals from TNF-family receptors (TNFRs).
- TRAF1 is unique, lacking a RING finger domain and exhibiting restricted expression in immune cells and epithelia.
Purpose of the Study:
- To review current knowledge on TRAF1, emphasizing findings from TRAF1-deficient mice.
- To explore the role of TRAF1 as a negative regulator of TNF-family receptor signaling.
- To discuss the potential of TRAFs as drug discovery targets.
Main Methods:
- Analysis of data from TRAF1-deficient (TRAF1(-/-)) mice.
- In vitro assessment of T cell receptor (TCR)-dependent T cell proliferation.
- In vivo evaluation of sensitivity to TNF-alpha-induced skin necrosis.
Main Results:
- TRAF1-deficient T cells exhibit hyper-responsiveness to TNF-alpha.
- Increased T cell proliferation rates were observed in TRAF1-deficient T cells in vitro.
- TRAF1-deficient mice showed heightened sensitivity to TNF-alpha-induced skin necrosis in vivo.
Conclusions:
- TRAF1 functions as a negative regulator of signaling pathways initiated by certain TNF-family receptors.
- TRAF1 deficiency leads to exaggerated responses to TNF-alpha.
- TRAFs present both opportunities and challenges as targets for therapeutic drug development.