TRAF6 deficiency promotes TNF-induced cell death through inactivation of GSK3beta.
TNF receptor-associated factor 6 (TRAF6) plays a key role in the regulation of innate immune responses by mediating signals from both TNF receptors (TNFRs) and interleukin-1 receptors (IL-1Rs)/Toll-like receptors (TLRs). Here, we define a new role for TRAF6 in antagonizing cell death during TNF signaling. In TRAF6-deficient 3T3 (T6(-/-) 3T3) cells, TNF stimulation leads to the accumulation of reactive oxygen species (ROS), which in turn results in prolonged c-Jun N-terminal kinase (JNK) activation and accelerated cell death. Furthermore, TNF-induced p65/RelA phosphorylation as well as transcriptional activity of nuclear factor-kappaB (NF-kappaB) was significantly downregulated in T6(-/-) 3T3 cells. Interestingly, TRAF6 deficiency leads to constitutive phosphorylation and inactivation of glycogen synthase kinase 3beta (GSK3beta). Restoration of GSK3beta activity through exogenous expression of a GSK3beta constitutive active form rescued cell death in TRAF6-null 3T3 cells. These data suggest a role for TRAF6 in the maintenance of cell survival by regulating GSK3beta activity in TNF signaling.
Yoon
K
K
Division of Life and Pharmaceutical Sciences, Center for Cell Signaling & Drug Discovery Research, College of Natural Sciences, Ewha Womans University, Seoul, Korea.
Jung
E J
EJ
Lee
S R
SR
Kim
J
J
Choi
Y
Y
Lee
S Y
SY
D016475:3T3 Cells; D000818:Animals; D016923:Cell Death; D002470:Cell Survival; D015536:Down-Regulation; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D051996:Transcription Factor RelA / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; C498144:Rela protein, mouse; D047992:TNF Receptor-Associated Factor 2; D048029:TNF Receptor-Associated Factor 6; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3