Rescue of TRAF3-null mice by p100 NF-kappa B deficiency.
Rescue of TRAF3-null mice by p100 NF-kappa B deficiency.
复制标题
p100 nf-kappa b缺陷营救traf3-null小鼠。
DOI：
10.1084/jem.20061166
复制
发表时间：
2006-10-30
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
核因子（NF）-κB转录因子的适当活化在调节基本生物过程（如细胞存活和增殖）以及炎症和免疫应答中是至关重要的。最近，NF-κB信号传导途径已被分类为经典途径和非经典途径，经典途径导致含有p50的NF-κB复合物的核转运，非经典途径涉及p100至p52的诱导加工以及含有p52的NF-κB复合物的形成（Bonizzi，G.，和M.卡琳2004. Trends Immunol.25：280-288）。我们证明肿瘤坏死因子（TNF）受体相关因子3（TRAF 3）的缺失导致组成性非经典NF-κB活性。重要的是，TRAF 3 −/− B细胞在体外培养过程中显示出细胞内粘附分子1的配体非依赖性上调和对自发凋亡的保护。此外，我们证明TRAF 3的缺失导致TRAF 3 −/−细胞中NF-κ B诱导激酶的大量积累。最后，我们发现TRAF 3缺陷小鼠的出生后早期致死率是由非经典NF-κB p100基因的复合缺失挽救的。因此，这些遗传数据清楚地表明TRAF 3是非经典NF-κB途径的关键负调节剂，并且非经典NF-κB途径的组成性激活导致TRAF 3缺陷小鼠的致死表型。
Proper activation of nuclear factor (NF)–κB transcription factors is critical in regulating fundamental biological processes such as cell survival and proliferation, as well as in inflammatory and immune responses. Recently, the NF-κB signaling pathways have been categorized into the canonical pathway, which results in the nuclear translocation of NF-κB complexes containing p50, and the noncanonical pathway, which involves the induced processing of p100 to p52 and the formation of NF-κB complexes containing p52 (Bonizzi, G., and M. Karin. 2004. Trends Immunol. 25:280–288). We demonstrate that loss of tumor necrosis factor (TNF) receptor–associated factor 3 (TRAF3) results in constitutive noncanonical NF-κB activity. Importantly, TRAF3−/− B cells show ligand-independent up-regulation of intracellular adhesion molecule 1 and protection from spontaneous apoptosis during in vitro culture. In addition, we demonstrate that loss of TRAF3 results in profound accumulation of NF-κB–inducing kinase in TRAF3−/− cells. Finally, we show that the early postnatal lethality observed in TRAF3-deficient mice is rescued by compound loss of the noncanonical NF-κB p100 gene. Thus, these genetic data clearly demonstrate that TRAF3 is a critical negative modulator of the noncanonical NF-κB pathway and that constitutive activation of the noncanonical NF-κB pathway causes the lethal phenotype of TRAF3-deficient mice.