Heat shock genes - integrating cell survival and death
Heat shock genes - integrating cell survival and death
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DOI：
10.1007/s12038-007-0059-3
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发表时间：
2007-04-01
影响因子：
2.9
通讯作者：
Lakhotia, Subhash C.
中科院分区：
文献类型：
--
作者：
Arya, Richa;Mallik, Moushami;Lakhotia, Subhash C.
热休克诱导的基因表达和其他细胞反应有助于限制应激造成的损伤，从而促进细胞恢复。细胞损伤也通过多种途径引发细胞凋亡。本文就主要热休克蛋白与凋亡通路组分的相互作用作一综述。Hsp90作为不稳定信号转导的伴侣，使其保持激活状态，与RIP和Akt相互作用，促进NF-kappa B介导的细胞凋亡抑制；此外，它还阻断凋亡途径中的某些步骤。Hsp70主要是抗凋亡的，它在抑制Bax易位进入线粒体、从线粒体释放细胞色素c、凋亡小体的形成和抑制启动物caspases的激活等几个层面上起作用。Hsp70还在凋亡级联中调控JNK、NF-kappa B和Akt信号通路。相反，Hsp60同时具有抗和促凋亡作用。胞质Hsp60阻止促凋亡蛋白Bax转位进入线粒体，从而促进细胞存活，但它也促进procaspase-3的成熟，这对于caspase介导的细胞死亡至关重要。我们最近的体内研究表明，针对黑腹果蝇Hsp60D的RNAi可以阻止诱导的细胞凋亡。Hsp27通过抑制细胞色素c和tnf介导的细胞死亡发挥其抗凋亡作用。α - β晶体蛋白抑制caspase-8和细胞色素c介导的caspase-3的激活。我们实验室的研究还表明，发育活性和应激诱导的非编码hsr - omega转录本的缺失或水平降低，可以隔离多种hnRNPs和相关的核rna结合蛋白，阻断果蝇诱导的凋亡。热休克蛋白对凋亡通路的调节反映了它们作为细胞网络中各种“枢纽”之间的“弱链接”的作用。另一方面，非编码rna凭借其与多种蛋白质结合的潜力，可以在这些网络中充当“枢纽”。鉴于生命系统的整体性，通常被认为主要在细胞存活途径中起作用的应激诱导基因在多个水平上抑制甚至促进细胞死亡途径，以确保细胞和/或生物体水平的稳态，这并不奇怪。显然，热休克基因的作用远不止帮助细胞在压力下生存。
Heat shock induced gene expression and other cellular responses help limit the damage caused by stress and thus facilitate cellular recovery. Cellular damage also triggers apoptotic cell death through several pathways. This paper briefly reviews interactions of the major heat shock proteins with components of the apoptotic pathways. Hsp90, which acts as a chaperone for unstable signal transducers to keep them poised for activation, interacts with RIP and Akt and promotes NF-kappa B mediated inhibition of apoptosis; in addition it also blocks some steps in the apoptotic pathways. Hsp70 is mostly anti-apoptotic and acts at several levels like inhibition of translocation of Bax into mitochondria, release of cytochrome c from mitochondria, formation of apoptosome and inhibition of activation of initiator caspases. Hsp70 also modulates JNK, NF-kappa B and Akt signaling pathways in the apoptotic cascade. In contrast, Hsp60 has both anti- and pro-apoptotic roles. Cytosolic Hsp60 prevents translocation of the pro-apoptotic protein Bax into mitochondria and thus promotes cell survival but it also promotes maturation of procaspase-3, essential for caspase mediated cell death. Our recent in vivo studies show that RNAi for the Hsp60D in Drosophila melanogaster prevents induced apoptosis. Hsp27 exerts its anti-apoptotic influence by inhibiting cytochrome c and TNF-mediated cell death. alpha beta crystallin suppresses caspase-8 and cytochrome c mediated activation of caspase-3. Studies in our laboratory also reveal that absence or reduced levels of the developmentally active as well as stress induced non-coding hsr omega transcripts, which are known to sequester diverse hnRNPs and related nuclear RNA-binding proteins, block induced apoptosis in Drosophila. Modulation of the apoptotic pathways by Hsps reflects their roles as "weak links" between various "hubs" in cellular networks. On the other hand, non-coding RNAs, by virtue of their potential to bind with multiple proteins, can act as "hubs" in these networks. In view of the integrative nature of living systems, it is not surprising that stress-induced genes, generally believed to primarily function in cell survival pathways, inhibit or even promote cell death pathways at multiple levels to ensure homeostasis at cell and/or organism level. The heat shock genes obviously do much more than merely help cells survive stress.