抑制蛋白复合物调节巨噬细胞脂肪酸组成、质膜堆积和脂筏介导的炎症信号传导

Christine E. Psaltis Matthews , Lynn A. Fussner , Michael Yaeger , Jim J. Aloor , Sky W. Reece , Brita J. Kilburg-Basnyat , Sanjay Varikuti , Bin Luo , Morgan Inks , Selin Sergin , Cameron A. Schmidt , P. Darrell Neufer , Edward Ross Pennington , Kelsey H. Fisher-Wellman , Saiful M. Chowdhury , Michael B. Fessler , Jenifer I. Fenton , Ethan J. Anderson , Saame Raza Shaikh , Kymberly M. Gowdy
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引用次数: 2

摘要

抑制素(PHB1和PHB2)是广泛表达的蛋白质,在多种生物过程中发挥关键作用,并共同形成环状PHB复合物,存在于富含磷脂的细胞区室中,包括脂筏。最近的研究表明PHB1是脂肪酸转运的介质,也是介导B淋巴细胞和肥大细胞信号转导的膜支架。然而,PHBs在巨噬细胞中的具体作用尚未得到表征,包括它们在脂肪酸摄取和脂筏介导的炎症信号传导中的作用。我们假设PHB复合物通过脂筏的形成调节巨噬细胞炎症信号传导。为了评估我们的假设,用针对PHB1、PHB2或扰乱对照(Scr)的shRNA转导RAW 264.7巨噬细胞,然后用脂多糖(LPS)或肿瘤坏死因子α(TNF-α)刺激,其激活脂筏依赖性受体信号传导(分别为CD14/TLR4和TNFR1)。PHB1敲低是致命的,而PHB2敲低(PHB2kd)也导致PHB1表达降低,导致核因子κB(NF-κB)激活减弱,随后产生细胞因子和趋化因子。PHB2kd巨噬细胞在基线和刺激后也具有降低的细胞表面TNFR1、CD14、TLR4和脂筏标记神经节苷脂GM1。LPS后,PHB2kd巨噬细胞不会增加细胞饱和、单不饱和和多不饱和脂肪酸的浓度。这伴随着脂筏形成的减少和质膜分子堆积的改变,进一步支持了PHB复合物在脂筏形成中的重要性。总之,这些数据表明PHBs通过维持脂肪酸组成和脂筏结构在调节巨噬细胞炎症信号传导中发挥着关键作用。摘要抑制素是在富含磷脂的细胞区室中发现的蛋白质,包括脂筏,在信号传导、转录和多种其他细胞功能中发挥重要作用。巨噬细胞是先天免疫反应的关键细胞,膜脂筏的存在是信号转导的组成部分,但抑制剂在巨噬细胞脂筏和相关信号传导中的作用尚不清楚。为了解决这个问题,产生了抑制蛋白敲低巨噬细胞,并分析了通过脂筏依赖性受体作用的脂多糖和肿瘤坏死因子α的反应。Prohibitin敲低巨噬细胞显著降低了细胞因子和趋化因子的产生、转录因子激活、受体表达、脂筏组装和膜堆积,并改变了脂肪酸重塑。这些数据表明,抑制剂通过调节脂肪酸组成和脂筏形成,在巨噬细胞炎症信号传导中发挥着新的作用。
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The prohibitin complex regulates macrophage fatty acid composition, plasma membrane packing, and lipid raft-mediated inflammatory signaling

Prohibitins (PHB1 and PHB2) are ubiquitously expressed proteins which play critical roles in multiple biological processes, and together form the ring-like PHB complex found in phospholipid-rich cellular compartments including lipid rafts. Recent studies have implicated PHB1 as a mediator of fatty acid transport as well as a membrane scaffold mediating B lymphocyte and mast cell signal transduction. However, the specific role of PHBs in the macrophage have not been characterized, including their role in fatty acid uptake and lipid raft-mediated inflammatory signaling. We hypothesized that the PHB complex regulates macrophage inflammatory signaling through the formation of lipid rafts. To evaluate our hypothesis, RAW 264.7 macrophages were transduced with shRNA against PHB1, PHB2, or scrambled control (Scr), and then stimulated with lipopolysaccharide (LPS) or tumor necrosis factor-alpha (TNF-α), which activate lipid raft-dependent receptor signaling (CD14/TLR4 and TNFR1, respectively). PHB1 knockdown was lethal, whereas PHB2 knockdown (PHB2kd), which also resulted in decreased PHB1 expression, led to attenuated nuclear factor-kappa-B (NF-κB) activation and subsequent cytokine and chemokine production. PHB2kd macrophages also had decreased cell surface TNFR1, CD14, TLR4, and lipid raft marker ganglioside GM1 at baseline and post-stimuli. Post-LPS, PHB2kd macrophages did not increase the concentration of cellular saturated, monounsaturated, and polyunsaturated fatty acids. This was accompanied by decreased lipid raft formation and modified plasma membrane molecular packing, further supporting the PHB complex's importance in lipid raft formation. Taken together, these data suggest a critical role for PHBs in regulating macrophage inflammatory signaling via maintenance of fatty acid composition and lipid raft structure.

Summary

Prohibitins are proteins found in phospholipid-rich cellular compartments, including lipid rafts, that play important roles in signaling, transcription, and multiple other cell functions. Macrophages are key cells in the innate immune response and the presence of membrane lipid rafts is integral to signal transduction, but the role of prohibitins in macrophage lipid rafts and associated signaling is unknown. To address this question, prohibitin knockdown macrophages were generated and responses to lipopolysaccharide and tumor necrosis factor-alpha, which act through lipid raft-dependent receptors, were analyzed. Prohibitin knockdown macrophages had significantly decreased cytokine and chemokine production, transcription factor activation, receptor expression, lipid raft assembly and membrane packing, and altered fatty acid remodeling. These data indicate a novel role for prohibitins in macrophage inflammatory signaling through regulation of fatty acid composition and lipid raft formation.

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来源期刊
Prostaglandins, leukotrienes, and essential fatty acids
Prostaglandins, leukotrienes, and essential fatty acids Clinical Biochemistry, Endocrinology, Diabetes and Metabolism
CiteScore
5.30
自引率
0.00%
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0
审稿时长
64 days
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