RAPID PROTEOLYSIS OF I-KAPPA-B-ALPHA IS NECESSARY FOR ACTIVATION OF TRANSCRIPTION FACTOR NF-KAPPA-B
RAPID PROTEOLYSIS OF I-KAPPA-B-ALPHA IS NECESSARY FOR ACTIVATION OF TRANSCRIPTION FACTOR NF-KAPPA-B
复制标题
DOI：
10.1038/365182a0
复制
发表时间：
1993-09-09
期刊：
影响因子：
64.8
通讯作者：
BAEUERLE, PA
中科院分区：
文献类型：
--
作者：
HENKEL, T;MACHLEIDT, T;BAEUERLE, PA
真核生物中的可诱导基因表达主要由转录激活蛋白的活性控制，例如NF-κ B（参考文献1-3），NF-κ B是用佛波醇酯、脂多糖4、白细胞介素-1和肿瘤坏死因子-α 5处理细胞后激活的因子。NF-κ B的激活涉及抑制性亚基IkappaB从与DNA结合亚基Rel-A（以前的p65）和p50的胞质复合物中释放（参考文献6，7）。无细胞实验表明，蛋白激酶C和其他激酶将磷酰基转移到IkappaB上，导致IkappaB的释放和随后的NF-κ B8 -10的活化。在这里，我们报告说，IkappaB-α（以前的MAD-3）11被降解后，与佛波酯，白细胞介素-1，脂多糖和肿瘤坏死因子-α刺激细胞，一个事件与活性NF-κ B的外观一致。用各种蛋白酶抑制剂或抗氧化剂处理细胞完全阻止了IkappaB-α的诱导性衰变以及NF-κ B的激活。我们的研究结果表明，NF-κ B的激活依赖于通过细胞质胰凝乳蛋白酶样蛋白酶诱导降解IkappaB-α。在完整细胞中，IkappaB-α的磷酸化显然不足以激活NF-κ B。
INDUCIBLE gene expression in eukaryotes is mainly controlled by the activity of transcriptional activator proteins, such as NF-kappaB (refs 1-3), a factor activated upon treatment of cells with phorbol esters, lipopolysaccharide4, interleukin-1 and tumour necrosis factor-alpha5. Activation of NF-kappaB involves release of the inhibitory subunit IkappaB from a cytoplasmic complex with the DNA-binding subunits Rel-A (formerly p65) and p50 (refs 6, 7). Cell-free experiments have suggested that protein kinase C and other kinases transfer phosphoryl groups onto IkappaB causing release of IkappaB and subsequent activation of NF-kappaB8-10. Here we report that IkappaB-alpha (formerly MAD-3)11 is degraded in cells after stimulation with phorbol ester, interleukin-1, lipopolysaccharide and tumour necrosis factor-alpha, an event coincident with the appearance of active NF-kappaB. Treatment of cells with various protease inhibitors or an antioxidant completely prevented the inducible decay of IkappaB-alpha as well as the activation of NF-kappaB. Our findings suggest that the activation of NF-kappaB relies on an inducible degradation of IkappaB-alpha through a cytoplasmic, chymotrypsin-like protease. In intact cells, phosphorylation of IkappaB-alpha is apparently not sufficient for activation of NF-kappaB.