Proteasome regulation of activation-induced T cell death.
Proteasome regulation of activation-induced T cell death.
复制标题
蛋白酶体调节激活诱导的 T 细胞死亡。
DOI：
10.1073/pnas.94.14.7515
复制
发表时间：
1997
影响因子：
11.1
通讯作者：
Ju,ST
中科院分区：
文献类型：
--
作者：
Cui,H;Matsui,K;Omura,S;Schauer,SL;Matulka,RA;Sonenshein,GE;Ju,ST
Lactacystin是一种仅抑制蛋白酶体中蛋白酶活性的微生物代谢产物，用于研究蛋白酶体在T细胞活化诱导的细胞死亡（AICD）中的作用。Lactacystin以剂量依赖性方式诱导T细胞杂交瘤（DO.11.10）中的DNA片段化和细胞凋亡。在1 - 10 μM之间，轻度细胞毒性lactacystin抑制在抗CD 3包被的威尔斯孔中培养的DO. 11. 10细胞的AICD。lactacystin可抑制IκBβ的降解和NF-κB（p50/RelA）向细胞核内的转位，这发生在抗CD 3激活后1.5小时。Lactacystin不抑制核转录因子Oct-1的表达。活化诱导的立即早期基因Nur 77和T细胞死亡基因CD 95（Fas）和CD 95配体（FasL）的表达受到抑制。FasL细胞毒活性的功能性表达和细胞表面Fas的增加也受到抑制。Lactacystin必须在激活后2小时内加入，以有效阻断AICD。此外，lactacystin未能抑制表达FasL的同种异体特异性细胞毒性效应细胞对DO.11.10的杀伤。这些观察结果强烈表明，IκBβ的蛋白酶体依赖性降解与AICD之间存在直接联系，这种联系通过FasL基因的激活和Fas基因的上调而发生。
Lactacystin, a microbial metabolite that inhibits protease activity only in the proteasome, was used to study the role of the proteasome in the activation-induced cell death (AICD) of T cells. Lactacystin induces DNA fragmentation and apoptosis in a T cell hybridoma (DO.11.10) in a dose-dependent manner. Between 1 and 10 μM, the mildly cytotoxic lactacystin inhibited the AICD of DO.11.10 cells cultured in anti-CD3-coated wells. Degradation of IκBβ and the translocation of the NF-κB (p50/RelA) into the nucleus, which occurred at 1.5 hr after anti-CD3 activation, were inhibited by lactacystin. Lactacystin did not inhibit the expression of nuclear transcription factor Oct-1. The activation-induced expression of the immediate–early gene, Nur77, and the T cell death genes, CD95 (Fas) and CD95 ligand (FasL), were inhibited. Functional expression of FasL cytotoxicity and the increase of cell surface Fas were also inhibited. Lactacystin must be added within 2 hr of activation to efficiently block AICD. In addition, lactacystin failed to inhibit the killing of DO.11.10 by FasL-expressing allo-specific cytotoxic effector cells. These observations strongly suggest a direct link between the proteasome-dependent degradation of IκBβ and the AICD that occurs through activation of the FasL gene and up-regulation of the Fas gene.