Hsp72 and stress kinase c-jun N-terminal kinase regulate the bid-dependent pathway in tumor necrosis factor-induced apoptosis
Hsp72 and stress kinase c-jun N-terminal kinase regulate the bid-dependent pathway in tumor necrosis factor-induced apoptosis
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DOI：
10.1128/mcb.22.10.3415-3424.2002
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发表时间：
2002-05-01
影响因子：
5.3
通讯作者：
Sherman, MY
中科院分区：
文献类型：
--
作者：
Gabai, VL;Mabuchi, K;Sherman, MY
主要的诱导型热休克蛋白Hsp 72已显示出保护细胞免受某些凋亡刺激。在这里，我们研究了热休克蛋白72介导的保护机制，从肿瘤坏死因子（TNF）诱导的原代培养IMR 90人成纤维细胞凋亡。热休克蛋白72暂时阻断细胞凋亡的TNF和永久保护细胞免受热休克。一个Hsp 72突变体（Hsp 72 DeltaEEVD）与删除的四个C-末端氨基酸，这是必不可少的伴侣功能，阻断TNF诱导的细胞凋亡的方式类似于正常的Hsp 72，但不抑制热休克诱导的死亡。因此，Hsp 72的伴侣活性对于抑制TNF诱导的细胞凋亡是必需的，但是对于保护免受热休克是必需的。在来自Bid基因敲除小鼠的成纤维细胞中，观察到TNF诱导的细胞凋亡的类似时间抑制。在这些细胞中，无论是正常的Hsp 72或Hsp 72 Δ EEVD赋予额外的保护凋亡，这表明Hsp 72特异性地影响Bid依赖性而不是Bid非依赖性凋亡途径。此外，正常的Hsp 72和DeltaHsp 72 EEVD抑制Bid激活和下游事件，包括细胞色素c的释放，半胱天冬酶3的激活和多聚ADP-核糖聚合酶的裂解。Hsp 72和DeltaHsp 72 EEVD均阻断TNF对应激激酶c-jun N-末端激酶（JNK）的激活，并且JNK的特异性抑制类似地暂时阻断Bid激活和下游凋亡事件。这些数据有力地表明，在TNF诱导的细胞凋亡中，Hsp 72通过抑制JNK特异性地干扰Bid依赖的细胞凋亡途径。
The major inducible heat shock protein Hsp72 has been shown to protect cells from certain apoptotic stimuli. Here we investigated the mechanism of Hsp72-mediated protection from tumor necrosis factor (TNF)-induced apoptosis of primary culture of IMR90 human fibroblasts. Hsp72 temporarily blocked apoptosis in response to TNF and permanently protected cells from heat shock. An Hsp72 mutant (Hsp72DeltaEEVD) with a deletion of the four C-terminal amino acids, which are essential for the chaperone function, blocked TNF-induced apoptosis in a manner similar to that of normal Hsp72 but did not inhibit heat shock-induced death. Therefore, the chaperone activity of Hsp72 is dispensable for suppression of TNF-induced apoptosis but is required for protection from heat shock. In fibroblasts derived from Bid knockout mice, similar temporal inhibition of TNF-induced apoptosis was seen. In these cells neither normal Hsp72 nor Hsp72DeltaEEVD conferred additional protection from apoptosis, suggesting that Hsp72 specifically affects Bid-dependent but not Bid-independent apoptotic pathways. Furthermore, both normal Hsp72 and DeltaHsp72EEVD inhibited Bid activation and downstream events, including release of cytochrome c, activation of caspase 3, and cleavage of poly-ADP-ribose polymerase. Both Hsp72 and DeltaHsp72EEVD blocked activation of the stress kinase c-jun N-terminal kinase (JNK) by TNF, and specific inhibition of JNK similarly temporarily blocked Bid activation and the downstream apoptotic events. These data strongly suggest that in TNF-induced apoptosis, Hsp72 specifically interferes with the Bid-dependent apoptotic pathway via inhibition of JNK.