Lymphotoxin-beta receptor signaling complex: role of tumor necrosis factor receptor-associated factor 3 recruitment in cell death and activation of nuclear factor kappaB.
The binding of heterotrimeric lymphotoxin, LT alpha1 beta2, to the LTbeta receptor (LTbeta R), a member of the tumor necrosis factor receptor (TNFR) superfamily, induces nuclear factor kappaB (NF-kappaB) activation and cell death in HT29 adenocarcinoma cells. We now show that treatment with LT alpha1 beta2 or agonistic LTbeta R antibodies causes rapid recruitment of TNFR-associated factor 3 (TRAF3) to the LTbeta R cytoplasmic domain. Further, stable overexpression of a TRAF3 mutant that lacks the RING and zinc finger domains inhibits LTbeta R-mediated cell death. The inhibition is specific for LTbeta R cell death signaling, since NF-kappaB activation by LT alpha1 beta2 and Fas-mediated apoptosis are not inhibited in the same cells. The mutant and endogenous TRAF3s are both recruited at equimolar amounts to the LTbeta R, suggesting that the mutant disrupts the function of the signaling complex. These results implicate TRAF3 as a critical component of the LTbeta R death signaling complex and indicate that at least two independent signaling pathways are initiated by LTbeta R ligation.
VanArsdale
T L
TL
Division of Biomedical Sciences, University of California, Riverside 92521, USA.
VanArsdale
S L
SL
Force
W R
WR
Walter
B N
BN
Mosialos
G
G
Kieff
E
E
Reed
J C
JC
Ware
C F
CF
D000230:Adenocarcinoma; D000906:Antibodies / Q000494:pharmacology; D001483:Base Sequence; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D017931:DNA Primers; D006801:Humans; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha / Q000494:pharmacology*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D014176:Protein Biosynthesis; D055503:Protein Multimerization; D011506:Proteins / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D017384:Sequence Deletion; D015398:Signal Transduction; D048008:TNF Receptor-Associated Factor 3; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D016335:Zinc Fingers; D019014:fas Receptor / Q000276:immunology / Q000502:physiology
D000906:Antibodies; D017931:DNA Primers; C505697:LTBR protein, human; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha; D016328:NF-kappa B; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D048008:TNF Receptor-Associated Factor 3; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor