TRAF6 deficiency promotes TNF-induced cell death through inactivation of GSK3β

K. Yoon, E. J. Jung, S. R. Lee, J. Kim, Y. Choi, S. Y. Lee

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23 Scopus citations

Abstract

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-κB (NF-κB) was significantly downregulated in T6-/- 3T3 cells. Interestingly, TRAF6 deficiency leads to constitutive phosphorylation and inactivation of glycogen synthase kinase 3β (GSK3β). Restoration of GSK3β activity through exogenous expression of a GSK3β 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 GSK3β activity in TNF signaling.

Original languageEnglish
Pages (from-to)730-738
Number of pages9
JournalCell Death and Differentiation
Volume15
Issue number4
DOIs
StatePublished - Apr 2008

Bibliographical note

Funding Information:
Acknowledgements. We thank Dr. Wen-Chen Yeh for providing TRAF2-deficient 3T3 cells, Matthew C. Walsh for providing TRAF6-/-MEFs, Dr. Toshio Kitamura for providing the Plat-E cell line, and Dr. Hong-Duk Um for providing Ref-1 antibody. This work was supported in part by the KOSEF grant M1-0641-35-0002 (SYL), by the Korea Research Foundation Grant funded by the Korean Government (MOEHRD) (KRF-2006-C00309), and by NCRC program of MOST/KOSEF (Grant no. R15-2006-020-00000-0) through the Center for Cell Signaling & Drug Discovery Research at Ewha Womans University. KY was supported by BK21 fellowship.

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