氧化固醇结合蛋白家族相互作用蛋白组的鉴定和功能研究
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摘要
一类含有与氧化固醇结合蛋白(OSBP)相关的配体结合域的蛋白家族已经在真核生物中被鉴定出来,这些蛋白,被命名为OSBP相关蛋白(OSBP-related proteins (ORPs))或者OSBP样蛋白(OSBP-like proteins(OSBPL))。对酿酒酵母中的ORPs研究结果表明这些蛋白在固醇的细胞内非囊泡运输、高尔基体上的分泌型小泡运输以及细胞极性的建立中起作用。对哺乳动物的ORPs功能研究显示ORPs在有很多方面都起作用：固醇和鞘磷脂代谢的整合,固醇运输,中性脂代谢的调节,微管依赖性内涵体／溶酶体运动的调控以及信号级联的调节。然而,对ORPs参与上述功能的机制的理解,尚未明了。在本研究中,我们构建了十二个人类ORPs基因的诱饵载体,利用这此诱饵载体筛选了人胚肾cDNA文库和来源于多种成人组织的Univerval文库,筛选出的与ORPs相互作用的蛋白质,功能大致涉及到以下方面：细胞信号传导、囊泡运输、脂代谢、细胞骨架调节蛋白,糖代谢,离子转运,及血液凝集等。我们选择了相关蛋白进行了详尽地功能研究。
通过GST-Pull down, Co-IP实验确证了ORP8与核孔复合体蛋白NUP62物理结合后。我们发现,在人类肝癌细胞系Huh7, NUP62参与了过表达ORP8对甾醇调控元件结合蛋白(SREBPs)核内含量的下调；腺病毒介导小鼠肝脏的ORP8过表达降低导致血浆和肝组织中胆固醇,磷脂和甘油三酯的下降(在血浆中分别为-34%,-26%,-37%,在肝组织中分别为-40%,-12%,-24%),这种下降与核内nSREBPs的下降一致。在Huh-7细胞中,过表达ORP8导致核内SREBPs的降低,SREBP-2靶基因mRNA的表达下降和胆固醇合成减少,而沉默ORP8增加SREBP-2靶基因mRNA的表达。这些实验揭示了ORP8是一个生物体脂质平衡新的调节者。
我们证明了ORP11与ORP9形成二聚体。ORP11缺乏FFAT模体或其它ER定位信号,通过产生的亲和纯化抗体,我们发现该这新蛋白的组织和细胞型特异表达模式,并证明了它在细胞中分布于高尔基体和晚期内体膜之间。我们分析了ORP11膜定位的决定因素,表明ORP9是ORP11定位到高尔基体的一个决定因素。过表达ORP9招募过表达的EGFP-ORP11到内质网和高尔基体上,沉默ORP9抑制了内源性ORP11在高尔基体上的定位。ORP9与ORP11可能形成二聚体作为一个脂质的感受器和转运子。
我们还进一步研究了内质网膜上三磷脂肌醇(IP3)受体ITPR1与ORP4之间的相互作用,通过Co-IP,双分子荧光互补(Bimolecular FluorescenceComplementation, BiFC)实验确证了这对相互作用。ITPR1是细胞内内质网上的钙离子通道,在人宫颈癌上皮细胞系HeLa, ORP4沉默后细胞质中[Ca2+]在Histamine的刺激下峰值下降,表明细胞质钙含量降低。初步实验显示ORP4干扰增加细胞在毒胡萝卜素诱导后的凋亡率。
Protein families characterized by a ligand binding domain related to that of oxysterol binding protein (OSBP) have been identified in eukaryotic species from yeast to humans. These proteins, designated OSBP-related (ORPs) or OSBP-likeproteins (OSBPL), have been implicated in various cellular functions. Data from our and other laboratories suggest that binding of sterol ligands may be a unifying theme. Work with Saccharomyces cerevisiae ORPs suggests a function of these proteins in the nonvesicular intracellular transport of sterols, in secretory vesicle transport from the Golgi complex, and in the establishment of cell polarity. Mammals have more ORP genes, and differential splicing substantially increases the complexity of the encoded protein family. Functional studies on mammalian ORPs point in different directions:integration of sterol and sphingomyelin metabolism, sterol transport, regulation of neutral lipid metabolism, control of the microtubule-dependent motility of endosomes/ lysosomes, and regulation of signaling cascades. However, the detailed mechanisms of their action have remained elusive. An important way of learning protein function is to analyze their interacting-protein partners. In this study, the interacting proteins of ORPs family have be screened by Yeast Two-Hybrid using Human Fetal Kidney cDNA library and Mate & Plate Library-Universal Human (Normalized) which used cDNA from a wide spectrum of human tissues. Results showed ORPs interacted with proteins involved in various cellular functions, including signaling transduction, lipid metabolism, vesicle transport, nuclear transport, ion transport, blood coagulation, carbohydrate metabolism, protein synthesis and protein degradation etc. Interesting interactions have been chosen and studied further.
The interaction of ORP8 and NUP62 has been confirmed by GST-Pull down and Co-IP. Moderate adenovirus-mediated overexpression of human ORP8 in mouse liver induced a decrease of cholesterol, phospholipids, and triglycerides in serum(-34%,-26%,-37%, respectively) and liver tissue (-40%,-12%,-24%, respectively), coinciding with reduction of hepatic nuclear (n)SREBP-1 and-2. Consistently, excess ORP8 reduced nSREBPs in HuH7 cells, and ORP8 overexpression or silencing suppressed or induced the expression of SREBP-2 target genes, respectively. The impact of overexpressed ORP8 on nSREBPs was shown to require a normal level of Nup62. Together, these experiments showed a new mechanism that ORP8 regulates cellular cholesterol homeostasis.
Further more, we showed that ORP9 and ORP11 formed dimer with Co-IP experiment. We carry out characterization of ORP11, a previously unexplored ORP family member which is devoid of a FFAT motif or other known ER targeting signal. Using an affinity-purified antiserum generated during this study, we report the tissue and cell-type specific expression patterns of this new protein and demonstrate that it distributes in cells between Golgi and late endosome membranes. Overexpressed ORP9 recruited EGFP-ORP11 to endoplasmic reticulum and Golgi, and ORP9 silencing inhibited ORP11 Golgi association. The results identify ORP11 as an OSBP homologue distributing at the Golgi-LE interface and define the ORP9-ORP11 dimer as a functional unit that may act as an intracellular lipid sensor or transporter.
We also confirmed the interaction of ORP4 and IP3 receptor(ITPR1) by Co-IP and Bimolecular Fluorescence Complementation (BiFC) experiment. ITPR1 is a Ca2+ channel localized in the membrane of Endoplasmic reticulum. Our primary data showed that the silencing of ORP4 in HeLa cell reduced Histamine-induced calcium release and enhanced apoptosis after treatment of thapsigargin.
通过GST-Pull down, Co-IP实验确证了ORP8与核孔复合体蛋白NUP62物理结合后。我们发现,在人类肝癌细胞系Huh7, NUP62参与了过表达ORP8对甾醇调控元件结合蛋白(SREBPs)核内含量的下调；腺病毒介导小鼠肝脏的ORP8过表达降低导致血浆和肝组织中胆固醇,磷脂和甘油三酯的下降(在血浆中分别为-34%,-26%,-37%,在肝组织中分别为-40%,-12%,-24%),这种下降与核内nSREBPs的下降一致。在Huh-7细胞中,过表达ORP8导致核内SREBPs的降低,SREBP-2靶基因mRNA的表达下降和胆固醇合成减少,而沉默ORP8增加SREBP-2靶基因mRNA的表达。这些实验揭示了ORP8是一个生物体脂质平衡新的调节者。
我们证明了ORP11与ORP9形成二聚体。ORP11缺乏FFAT模体或其它ER定位信号,通过产生的亲和纯化抗体,我们发现该这新蛋白的组织和细胞型特异表达模式,并证明了它在细胞中分布于高尔基体和晚期内体膜之间。我们分析了ORP11膜定位的决定因素,表明ORP9是ORP11定位到高尔基体的一个决定因素。过表达ORP9招募过表达的EGFP-ORP11到内质网和高尔基体上,沉默ORP9抑制了内源性ORP11在高尔基体上的定位。ORP9与ORP11可能形成二聚体作为一个脂质的感受器和转运子。
我们还进一步研究了内质网膜上三磷脂肌醇(IP3)受体ITPR1与ORP4之间的相互作用,通过Co-IP,双分子荧光互补(Bimolecular FluorescenceComplementation, BiFC)实验确证了这对相互作用。ITPR1是细胞内内质网上的钙离子通道,在人宫颈癌上皮细胞系HeLa, ORP4沉默后细胞质中[Ca2+]在Histamine的刺激下峰值下降,表明细胞质钙含量降低。初步实验显示ORP4干扰增加细胞在毒胡萝卜素诱导后的凋亡率。
Protein families characterized by a ligand binding domain related to that of oxysterol binding protein (OSBP) have been identified in eukaryotic species from yeast to humans. These proteins, designated OSBP-related (ORPs) or OSBP-likeproteins (OSBPL), have been implicated in various cellular functions. Data from our and other laboratories suggest that binding of sterol ligands may be a unifying theme. Work with Saccharomyces cerevisiae ORPs suggests a function of these proteins in the nonvesicular intracellular transport of sterols, in secretory vesicle transport from the Golgi complex, and in the establishment of cell polarity. Mammals have more ORP genes, and differential splicing substantially increases the complexity of the encoded protein family. Functional studies on mammalian ORPs point in different directions:integration of sterol and sphingomyelin metabolism, sterol transport, regulation of neutral lipid metabolism, control of the microtubule-dependent motility of endosomes/ lysosomes, and regulation of signaling cascades. However, the detailed mechanisms of their action have remained elusive. An important way of learning protein function is to analyze their interacting-protein partners. In this study, the interacting proteins of ORPs family have be screened by Yeast Two-Hybrid using Human Fetal Kidney cDNA library and Mate & Plate Library-Universal Human (Normalized) which used cDNA from a wide spectrum of human tissues. Results showed ORPs interacted with proteins involved in various cellular functions, including signaling transduction, lipid metabolism, vesicle transport, nuclear transport, ion transport, blood coagulation, carbohydrate metabolism, protein synthesis and protein degradation etc. Interesting interactions have been chosen and studied further.
The interaction of ORP8 and NUP62 has been confirmed by GST-Pull down and Co-IP. Moderate adenovirus-mediated overexpression of human ORP8 in mouse liver induced a decrease of cholesterol, phospholipids, and triglycerides in serum(-34%,-26%,-37%, respectively) and liver tissue (-40%,-12%,-24%, respectively), coinciding with reduction of hepatic nuclear (n)SREBP-1 and-2. Consistently, excess ORP8 reduced nSREBPs in HuH7 cells, and ORP8 overexpression or silencing suppressed or induced the expression of SREBP-2 target genes, respectively. The impact of overexpressed ORP8 on nSREBPs was shown to require a normal level of Nup62. Together, these experiments showed a new mechanism that ORP8 regulates cellular cholesterol homeostasis.
Further more, we showed that ORP9 and ORP11 formed dimer with Co-IP experiment. We carry out characterization of ORP11, a previously unexplored ORP family member which is devoid of a FFAT motif or other known ER targeting signal. Using an affinity-purified antiserum generated during this study, we report the tissue and cell-type specific expression patterns of this new protein and demonstrate that it distributes in cells between Golgi and late endosome membranes. Overexpressed ORP9 recruited EGFP-ORP11 to endoplasmic reticulum and Golgi, and ORP9 silencing inhibited ORP11 Golgi association. The results identify ORP11 as an OSBP homologue distributing at the Golgi-LE interface and define the ORP9-ORP11 dimer as a functional unit that may act as an intracellular lipid sensor or transporter.
We also confirmed the interaction of ORP4 and IP3 receptor(ITPR1) by Co-IP and Bimolecular Fluorescence Complementation (BiFC) experiment. ITPR1 is a Ca2+ channel localized in the membrane of Endoplasmic reticulum. Our primary data showed that the silencing of ORP4 in HeLa cell reduced Histamine-induced calcium release and enhanced apoptosis after treatment of thapsigargin.
引文
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