A novel leucine-rich repeat protein (LRR-1): potential involvement in 4-1BB-mediated signal transduction.
4-1BB, a member of the tumor necrosis factor receptor (TNFR) superfamily, is induced on CD4+ and CD8+ T cells upon engagement of the T cell receptor (TCR)/ CD3 complex with the antigen bound to MHC. 4-1BB plays an important role in transmitting costimulatory signal during T cell activation. However, 4-1BB-mediatded signal transduction pathways have remained elusive. We conducted the yeast two-hybrid screening to identify intracellular signaling molecules that associate with 4-1BB. A novel leucine-rich repeat (LRR)-containing protein, herein named LRR-1, was found to specifically interact with the cytoplasmic domain of 4-1BB. Overexpression of LRR-1 suppressed the activation of NF-KB induced by 4-1BB or TNF receptor-associated factor (TRAF) 2. In addition, LRR-1 down-regulated JNK1 activity was induced by 4-1BB. These results indicate that LRR-1 negatively regulates the 4-1BB-mediated signaling cascades which result in the activation of NF-kappaB and JNK1.
Jang
L K
LK
National Institute of Allergy and Infectious Diseases, National Institute of Health, Bethesda, MD 20892, USA.
Lee
Z H
ZH
Kim
H H
HH
Hill
J M
JM
Kim
J D
JD
Kwon
B S
BS
D000595:Amino Acid Sequence; D015703:Antigens, CD; D003001:Cloning, Molecular; D015536:Down-Regulation; D006801:Humans; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D020449:Repetitive Sequences, Amino Acid / Q000235:genetics; D012097:Repressor Proteins; D015398:Signal Transduction / Q000502:physiology*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D020798:Two-Hybrid System Techniques
D015703:Antigens, CD; C464446:LRR1 protein, human; D016328:NF-kappa B; D011506:Proteins; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; D012097:Repressor Proteins; C505714:TNFRSF9 protein, human; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases