Regulation of the subcellular localization of tumor necrosis factor receptor-associated factor (TRAF)2 by TRAF1 reveals mechanisms of TRAF2 signaling.
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 RING finger-dependent process, which enables the activation of downstream signaling cascades including c-Jun NH(2)-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 cyto-skeletal 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.
Arron
Joseph R
JR
Tri-Institutional MD-PhD Program, The Rockefeller University, New York, NY 10021, USA.
Pewzner-Jung
Yael
Y
Walsh
Matthew C
MC
Kobayashi
Takashi
T
Choi
Yongwon
Y
D000595:Amino Acid Sequence; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology; D002478:Cells, Cultured; D003001:Cloning, Molecular; D003713:Dendritic Cells / Q000276:immunology; D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D011506:Proteins / Q000032:analysis / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000032:analysis / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013347:Subcellular Fractions / Q000378:metabolism; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; D014162:Transfection
D019013:CD40 Antigens; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010446:Peptide Fragments; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; D023201:CD40 Ligand; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases