Detergent-Resistant Microdomains Determine the Localization of σ-1 Receptors to the Endoplasmic Reticulum-Mitochondria Junction
Detergent-Resistant Microdomains Determine the Localization of σ-1 Receptors to the Endoplasmic Reticulum-Mitochondria Junction
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DOI：
10.1124/mol.109.062539
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发表时间：
2010-04-01
影响因子：
3.6
通讯作者：
Fujimoto, Michiko
中科院分区：
文献类型：
--
作者：
Hayashi, Teruo;Fujimoto, Michiko
结合多种合成和内源性化合物的σ-1受体（Sig-1 R）与多种人类疾病如药物成瘾、抑郁症、神经变性疾病、疼痛相关疾病和癌症的病理生理学有关。Sig-1 Rs是近年来发现的一种新型配体调控的分子伴侣。尽管Sig-1 R主要在与线粒体并列的内质网（ER）亚结构域表达[即，与MAM相关的ER膜（MAM）]，它们动态地改变细胞分布，从而调节MAM特异性蛋白和质膜蛋白。然而，是什么决定了Sig-1 R在MAM的位置以及受体易位是如何启动的尚不清楚。在这里，我们报告说，耐洗涤剂膜（DRM）发挥了重要作用，在锚定Sig-1 Rs的MAM。MAM，这是高度能够积累神经酰胺，富含胆固醇和简单的鞘脂，从而形成Triton X-114抗性DRM。Sig-1 R与MAM衍生的DRM相关，但与来自微粒体的DRM无关。脂质覆盖测定发现，溶解的Sig-1 R优先与简单的鞘脂如神经酰胺结合。通过降低胆固醇或抑制ER神经酰胺的从头合成来破坏DRM，大大降低了DRM上的Sig-1 R，并导致Sig-1 R从MAM易位到ER脑池。这些发现表明，MAM，轴承胆固醇和神经酰胺富集的微域在ER，可能会使用微域锚Sig-1 R的位置，因此，它的阶段Sig-1 R在ER-线粒体连接。
sigma-1 receptors (Sig-1Rs) that bind diverse synthetic and endogenous compounds have been implicated in the pathophysiology of several human diseases such as drug addiction, depression, neurodegenerative disorders, pain-related disorders, and cancer. Sig-1Rs were identified recently as novel ligand-operated molecular chaperones. Although Sig-1Rs are predominantly expressed at endoplasmic reticulum (ER) subdomains apposing mitochondria [i.e., the mitochondria-associated ER membrane (MAM)], they dynamically change the cellular distribution, thus regulating both MAM-specific and plasma membrane proteins. However, what determines the location of Sig-1R at the MAM and how the receptor translocation is initiated is unknown. Here we report that the detergent-resistant membranes (DRMs) play an important role in anchoring Sig-1Rs to the MAM. The MAM, which is highly capable of accumulating ceramides, is enriched with both cholesterol and simple sphingolipids, thus forming Triton X-114-resistant DRMs. Sig-1Rs associate with MAM-derived DRMs but not with those from microsomes. A lipid overlay assay found that solubilized Sig-1Rs preferentially associate with simple sphingolipids such as ceramides. Disrupting DRMs by lowering cholesterol or inhibiting de novo synthesis of ceramides at the ER largely decreases Sig-1R at DRMs and causes translocation of Sig-1R from the MAM to ER cisternae. These findings suggest that the MAM, bearing cholesterol and ceramide-enriched microdomains at the ER, may use the microdomains to anchor Sig-1Rs to the location; thus, it serves to stage Sig-1R at ER-mitochondria junctions.