Loss of a gimap/ian gene leads to activation of NF-κB through a MAPK-dependent pathway
Loss of a gimap/ian gene leads to activation of NF-κB through a MAPK-dependent pathway
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DOI：
10.1016/j.molimm.2006.02.014
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发表时间：
2007-01-01
影响因子：
3.6
通讯作者：
Scheinman, Robert I.
中科院分区：
文献类型：
--
作者：
Kupfer, Rene;Lang, Julie;Scheinman, Robert I.
易患糖尿病的生物育种 (BB-DP) 大鼠含有 lyp 突变，该突变会导致淋巴细胞减少，并促进某些大鼠品系中 T 细胞介导的胰腺自身免疫攻击的进展。该突变已被定位到与人类 Gimap5/Ian5 具有同源性的基因，并导致该蛋白质的截短和活性丧失。由于该蛋白缺失而导致淋巴细胞减少状态，因此有人提出 Gimap5 具有抗凋亡功能。之前我们描述了由 Gimap5 功能丧失介导的不完全激活的额外表型。在这里，我们进一步表征了这种不完全激活表型，并绘制了导致激活的潜在信号转导途径。我们发现 Gimap5 动物中外周 T 细胞上的 CD5 表达升高，而两种品系之间的胸腺细胞表达保持相似。此外，我们发现与未刺激的野生型 T 细胞相比，未刺激的 Gimap5 突变 T 细胞中 NF-kappa B 而不是 NFAT 被激活。将这种激活映射到其上游来源，我们发现 NF-kappa B 的激活与 IKK 的激活相关。使用多种激酶抑制剂，我们进一步将 IKK 的增加映射到 MEK 激活的增加。最后，为了反驳激活是淋巴细胞减少环境间接结果的可能性，我们创建了骨髓嵌合体，其中 Gimap5 突变 T 细胞在正常环境中发育，并表明这些细胞保留了其激活的表型。总之，我们将这些数据解释为证明 Gimap5 丢失引起的激活是一种细胞内在现象，部分是由 IKK 的 MEK 依赖性激活引起的。反过来，这表明 Gimap5 具有促进 T 细胞存活和静止的功能，并且这些途径在生化上是相关的。 (c) 2006 Elsevier Ltd. 保留所有权利。
The diabetes-prone biobreeding (BB-DP) rat contains the lyp mutation which results in lymphopenia and promotes the progression of a T cell-mediated autoimmune attack of the pancreas in certain rat strains. This mutation has been mapped to a gene which bears homology to human Gimap5/Ian5 and results in the truncation and loss of activity of this protein. The lymphopenic state induced by the loss of this protein has led to the proposal that Gimap5 has an anti-apoptotic function. Previously we described an additional phenotype of incomplete activation mediated by the loss of Gimap5 function. Here we further characterize this incomplete activation phenotype and map a potential signal transduction pathway leading to activation. We show that CD5 expression on peripheral T cells is elevated in Gimap5 animals, while thymocyte expression remains similar between the two strains. Additionally, we show that NF-kappa B but not NFAT is activated in unstimulated Gimap5 mutant T cells as compared to unstimulated wild type T cells. Mapping this activation to its upstream source we show that activation of NF-kappa B is correlated with an activation of IKK. Using a variety of kinase inhibitors we further map this increase in IKK to an increase in MEK activation. Finally, to counter the possibility that activation is an indirect consequence of the lymphopenic environment, we created bone marrow chimeras in which Gimap5 mutant T cells developed in a normal environment and show that these cells retain their activated phenotype. Together, we interpret these data as demonstrating that the activation caused by loss of Gimap5 is a cell intrinsic phenomenon caused, in part, by a MEK-dependent activation of IKK. This, in turn, would suggest that Gimap5 functions to promote both T cell survival and quiescence and that these pathways are biochemically linked. (c) 2006 Elsevier Ltd. All rights reserved.