期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 196, 期 7, 页码 923-934出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20020774
关键词
CD40; dendritic cell; lipid rafts; NF-kappa B; JNK
资金
- NIAID NIH HHS [AI-44264, R01 AI044264] Funding Source: Medline
- NIGMS NIH HHS [T32 GM007739] Funding Source: Medline
Tumor necrosis factor receptor-associated factor (TRAF)2 is a critical adaptor molecule for tumor necrosis factor (TNF) receptors in inflammatory and immune signaling. Upon receptor engagement, TRAF2 is recruited to CD40 and translocates to lipid rafts in a KING finger-dependent process, which enables the activation of downstream signaling cascades including c-Jun NH2-terminal kinase (JNK) and nuclear factor (NF)-kappaB. Although TRAF1 can displace TRAF2 and CD40 from raft fractions, it promotes the ability of TRAF2 activate signaling over a sustained period of time. Removal of the RING finger of TRAF2 prevents its translocation into detergent-insoluble complexes and renders it dominant negative for signaling. TRAF1(-/-) dendritic cells show attenuated responses to secondary stimulation by TRAF2-dependent factors and increased stimulus-dependent TRAF2 degradation. Replacement of the RING finger of TRAF2 with a raft-targeting signal restores JNK activation and association with the cytoskeletal protein Filamin, but not NF-kappaB activation. These findings offer insights into the mechanism of TRAF2 signaling and identify a physiological role for TRAF1 as a regulator of the subcellular localization of TRAF2.
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