Jang L K, Lee Z H, Kim H H, Hill J M, Kim J D, Kwon B S
National Institute of Allergy and Infectious Diseases, National Institute of Health, Bethesda, MD 20892, USA.
Mol Cells. 2001 Dec 31;12(3):304-12.
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.
4-1BB是肿瘤坏死因子受体（TNFR）超家族的成员，当T细胞受体（TCR）/CD3复合物与结合在MHC上的抗原结合时，它在CD4+和CD8+T细胞上被诱导表达。4-1BB在T细胞激活过程中传递共刺激信号方面发挥着重要作用。然而，4-1BB介导的信号转导途径仍然不清楚。我们进行了酵母双杂交筛选，以鉴定与4-1BB相关的细胞内信号分子。一种新的富含亮氨酸重复序列（LRR）的蛋白质，在此命名为LRR-1，被发现与4-1BB的胞质结构域特异性相互作用。LRR-1的过表达抑制了由4-1BB或肿瘤坏死因子受体相关因子（TRAF）2诱导的NF-κB的激活。此外，LRR-1下调了由4-1BB诱导的JNK1活性。这些结果表明，LRR-1负向调节4-1BB介导的信号级联反应，而该信号级联反应会导致NF-κB和JNK1的激活。
