FAST is a survival protein that senses mitochondrial stress and modulates TIA-1-regulated changes in protein expression
FAST is a survival protein that senses mitochondrial stress and modulates TIA-1-regulated changes in protein expression
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DOI：
10.1128/mcb.24.24.10718-10732.2004
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发表时间：
2004-12-01
影响因子：
5.3
通讯作者：
Anderson, P
中科院分区：
文献类型：
--
作者：
Li, W;Simarro, M;Anderson, P
Fas激活的丝氨酸/苏氨酸磷酸蛋白(FAST)被拴在线粒体膜外膜上，在那里它与bclX-L(17)相互作用。在这里，我们表明，RNA干扰介导的敲除内源性FAST导致细胞凋亡，而过表达的重组FAST抑制Fas和UV诱导的细胞凋亡，表明FAST是一种生存蛋白。FAST的抗凋亡作用是通过与翻译沉默分子TIA-1的相互作用来调节的：缺乏TIA-1结合域的FAST突变体不抑制细胞凋亡，过表达的重组TIA-1抑制FAST的抗凋亡作用。因为FAST的抗凋亡作用需要持续的蛋白质合成，我们假设FAST可能通过阻止TIA-1介导的编码凋亡抑制物的mRNAs沉默来发挥作用。与这一假设一致，FAST促进共转染报告蛋白的表达，这一过程需要其TIA-1结合结构域，并被过表达的重组TIA-1抑制。更引人注目的是，重组FAST增加了内源性CIAP-1和XIAP在HeLa细胞中的表达，但不增加GAPDH的表达。由于FAST是从Fas或UV诱导的细胞凋亡的线粒体中释放出来的，我们认为FAST是线粒体应激的传感器，调节TIA-1调节的转录后应激反应程序。
The Fas-activated serine/threonine phosphoprotein (FAST) is tethered to the outer mitochondrial membrane, where it interacts with BCL-X-L (17). Here we show that RNA interference-mediated knockdown of endogenous FAST results in apoptosis, whereas overexpressed recombinant FAST inhibits Fas- and UV-induced apoptosis, indicating that FAST is a survival protein. The antiapoptotic effects of FAST are regulated by interactions with the translational silencer TIA-1: a FAST mutant lacking its TIA-1-binding domain does not inhibit apoptosis, and overexpressed recombinant TIA-1 inhibits the antiapoptotic effects of FAST. Because the antiapoptotic effects of FAST require ongoing protein synthesis, we hypothesized that FAST might function by preventing TIA-1-mediated silencing of mRNAs encoding inhibitors of apoptosis. Consistent with this hypothesis, FAST promotes the expression of cotransfected reporter proteins, a process that requires its TIA-1-binding domain and is inhibited by overexpressed recombinant TIA-1. More compellingly, recombinant FAST increases the expression of endogenous cIAP-1 and XIAP, but not GAPDH, in transfected HeLa cells. Because FAST is released from mitochondria in cells undergoing Fas- or UV-induced apoptosis, we propose that FAST serves as a sensor of mitochondrial stress that modulates a TIA-1-regulated posttranscriptional stress response program.