TRAF1: lord without a RING.
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.
Zapata
Juan M
JM
Burnham Institute, La Jolla, CA 92037, USA. jzapata@burnham.org
Reed
John C
JC
D000818:Animals; D006801:Humans; D011506:Proteins / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D047990:TNF Receptor-Associated Factor 1
D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; D047990:TNF Receptor-Associated Factor 1