A NOVEL SIGNAL-TRANSDUCTION PATHWAY FROM THE ENDOPLASMIC-RETICULUM TO THE NUCLEUS IS MEDIATED BY TRANSCRIPTION FACTOR NF-KAPPA-B
A NOVEL SIGNAL-TRANSDUCTION PATHWAY FROM THE ENDOPLASMIC-RETICULUM TO THE NUCLEUS IS MEDIATED BY TRANSCRIPTION FACTOR NF-KAPPA-B
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DOI：
10.1002/j.1460-2075.1995.tb07256.x
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发表时间：
1995-06-01
期刊：
影响因子：
11.4
通讯作者：
BAEUERLE, PA
中科院分区：
文献类型：
--
作者：
PAHL, HL;BAEUERLE, PA
诱导型高级真核转录因子NF-κ B可被多种外部刺激激活，包括炎性细胞因子、病毒和细菌感染以及紫外线照射。在此，我们表明由内质网（ER）中蛋白质积累引起的内应力也诱导NF-κ B DNA结合以及κ B依赖性基因表达，这在不存在轻链的情况下表达免疫球蛋白μ链时以及通过用已知引起ER应激的几种试剂（例如衣霉素、布雷菲德菌素A、2-脱氧葡萄糖和毒胡萝卜素）处理细胞时观察到。转录因子AP-1在类似条件下被弱诱导，NF-κ B亚基的过表达不影响编码grp 78/BiP的基因的表达，grp 78/BiP是由各种形式的ER应激诱导的蛋白质。同样，诱导grp 78/BiP表达的葡萄糖苷酶抑制剂栗精胺不能激活NF-κ B，而抗氧化剂二硫苏糖醇增加grp 78/BiP表达但阻止NF-κ B的激活。NF-κ B B参与了一个新的ER核信号转导途径，不同于先前描述的未折叠蛋白反应。我们提供的证据表明，ER可以产生至少两种不同的信号，以响应功能障碍。一种是由未折叠蛋白质的存在而发出的，另一种是响应于细胞器的过载而发出的，例如通过分泌蛋白质的过表达。
The inducible, higher eukaryotic transcription factor NF-kappa B is activated by a variety of external stimuli including inflammatory cytokines, viral and bacterial infection and UV irradiation, Here we show that internal stress, caused by the accumulation of proteins in the endoplasmic reticulum (ER), also induces NF-kappa B DNA binding as well as kappa B-dependent gene expression, This was observed upon expression of immunoglobulin mu chains in the absence of light chains and by treatment of cells with several agents known to cause ER stress, such as tunicamycin, brefeldin A, 2-deoxyglucose and thapsigsargin, The transcription factor AP-1 was weakly induced under similar conditions, Overexpression of NF-kappa B subunits did not influence expression of the gene encoding grp78/BiP, a protein induced by various forms of ER stress, Likewise, the glucosidase inhibitor castanospermine, which induced grp78/BiP expression, failed to activate NF-kappa B, while the antioxidant dithiothreitol augmented grp78/BiP expression but prevented activation of NF-kappa B, Hence, NF-kappa B participates in a novel ER-nuclear signal transduction pathway distinct from the unfolded-protein-response described previously, We provide evidence that the ER can produce at least two distinct signals in response to a functional impairment. One is emitted by the presence of unfolded proteins, the other in response to overloading of the organelle, for example through the overexpression of secretory proteins.