Retinoid X receptor regulates Nur77/thyroid hormone receptor 3-dependent apoptosis by modulating its nuclear export and mitochondrial targeting
Retinoid X receptor regulates Nur77/thyroid hormone receptor 3-dependent apoptosis by modulating its nuclear export and mitochondrial targeting
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DOI：
10.1128/mcb.24.22.9705-9725.2004
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发表时间：
2004-11-01
影响因子：
5.3
通讯作者：
Zhang, XK
中科院分区：
文献类型：
--
作者：
Cao, XH;Liu, W;Zhang, XK
视黄嘌呤X受体（RXR）在调节细胞内受体信号通路中起核心作用，作为许多核受体的普遍异二聚化伙伴，包括孤儿受体Nur77（也称为甲状腺激素受体3或NGFI-B），其从细胞核易位到线粒体，在那里与bcl2相互作用诱导细胞凋亡。在这里，我们报道RXRalpha是Nur77核输出和线粒体靶向所必需的，通过其独特的异源二聚化，这是由位于dna结合域的二聚化界面介导的。rxrα的作用归因于其羧基末端区域存在假定的核输出序列（NES）。rxrα配体通过诱导rxrα同二聚化或改变rxrα /Nur77异二聚化来抑制NES活性。rxrα与视黄酸受体或维生素D受体异二聚化也可使rxrα NES沉默。一致地，我们能够证明RXR α /Nur77异源二聚体的线粒体靶向及其诱导凋亡被RXR配体有效地抑制。总之，我们的研究结果揭示了RXRalpha的一种新的非基因分型功能及其参与nur77依赖性凋亡通路的调节。
Retinoid X receptor (RXR) plays a central role in the regulation of intracellular receptor signaling pathways by acting as a ubiquitous heterodimerization partner of many nuclear receptors, including the orphan receptor Nur77 (also known as thyroid hormone receptor 3 or NGFI-B), which translocates from the nucleus to mitochondria, where it interacts with Bcl-2 to induce apoptosis. Here, we report that RXRalpha is required for nuclear export and mitochondrial targeting of Nur77 through their unique heterodimerization that is mediated by dimerization interfaces located in their DNA-binding domain. The effects of RXRalpha are attributed to a putative nuclear export sequence (NES) present in its carboxyl-terminal region. RXRalpha ligands suppress NES activity by inducing RXRalpha homodimerization or altering RXRalpha/Nur77 heterodimerization. The RXRalpha NES is also silenced by RXRalpha heterodimerization with retinoic acid receptor or vitamin D receptor. Consistently, we were able to show that the mitochondrial targeting of the RXRalpha/Nur77 heterodimer and its induction of apoptosis are potently inhibited by RXR ligands. Together, our results reveal a novel nongenotropic function of RXRalpha and its involvement in the regulation of the Nur77-dependent apoptotic pathway.