Proteomic Analysis of GLUT4 Storage Vesicles Reveals Tumor Suppressor Candidate 5 (TUSC5) as a Novel Regulator of Insulin Action in Adipocytes.
Proteomic Analysis of GLUT4 Storage Vesicles Reveals Tumor Suppressor Candidate 5 (TUSC5) as a Novel Regulator of Insulin Action in Adipocytes.
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GLUT4储存囊泡的蛋白质组学分析揭示了抑制肿瘤候选者5（TUSC5）是脂肪细胞中胰岛素作用的新调节剂。
DOI：
10.1074/jbc.m115.657361
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发表时间：
2015-09-25
期刊：
影响因子：
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通讯作者：
James DE
中科院分区：
文献类型：
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作者：
Fazakerley DJ;Naghiloo S;Chaudhuri R;Koumanov F;Burchfield JG;Thomas KC;Krycer JR;Prior MJ;Parker BL;Murrow BA;Stöckli J;Meoli CC;Holman GD;James DE
背景：我们寻找胰岛素刺激的脂肪细胞葡萄糖转运的新调节剂。结果如下：肿瘤抑制因子候选5（TUSC5）与GLUT4共定位，操纵TUSC5表达水平影响胰岛素调节的葡萄糖转运。结论：TUSC 5是一种新的胰岛素刺激的葡萄糖转运调节因子。意义：TUSC 5有助于脂肪细胞中PPARγ激动剂的胰岛素增敏作用。胰岛素信号通过调节葡萄糖转运蛋白4（GLUT 4）从专门的细胞内区室（称为GLUT 4储存囊泡（GSV））运输到质膜来增强葡萄糖转运。通过质谱对GSV进行蛋白质组学分析，发现这些囊泡中富集了59种蛋白质。我们测量了胰岛素刺激后这些蛋白质中23种的丰度降低，并将其指定为高置信度GSV蛋白质。这些包括已建立的GSV蛋白，如GLUT4和胰岛素反应性氨肽酶，以及先前未报告定位于GSV的六种蛋白。肿瘤抑制因子候选物5（TUSC5）被证明是一种新的GSV蛋白，其响应于胰岛素而在质膜上经历了3.7倍的丰度增加。siRNA介导的TUSC5敲低降低了胰岛素刺激的葡萄糖摄取，尽管TUSC5的过表达具有相反的效果，暗示TUSC5是脂肪细胞中胰岛素刺激的葡萄糖转运的正调节剂。用TNFα孵育脂肪细胞引起胰岛素抵抗和伴随的TUSC 5减少。与以前的研究一致，过氧化物酶体增殖物激活受体（PPAR）γ激动剂逆转TNFα诱导的胰岛素抵抗。TUSC5的表达是必需的，但不足以逆转胰岛素抵抗。这些发现在功能上将TUSC 5与脂肪细胞中的GLUT 4运输、胰岛素作用、胰岛素抵抗和PPARγ作用联系起来。需要进一步的研究来确定TUSC5在脂肪细胞中的确切作用。
Background: We searched for novel regulators of insulin-stimulated glucose transport in adipocytes. Results: Tumor suppressor candidate 5 (TUSC5) colocalized with GLUT4, and manipulation of TUSC5 expression levels affected insulin-regulated glucose transport. Conclusion: TUSC5 is a novel regulator of insulin-stimulated glucose transport. Significance: TUSC5 contributes to insulin-sensitizing effects of PPARγ agonists in adipocytes. Insulin signaling augments glucose transport by regulating glucose transporter 4 (GLUT4) trafficking from specialized intracellular compartments, termed GLUT4 storage vesicles (GSVs), to the plasma membrane. Proteomic analysis of GSVs by mass spectrometry revealed enrichment of 59 proteins in these vesicles. We measured reduced abundance of 23 of these proteins following insulin stimulation and assigned these as high confidence GSV proteins. These included established GSV proteins such as GLUT4 and insulin-responsive aminopeptidase, as well as six proteins not previously reported to be localized to GSVs. Tumor suppressor candidate 5 (TUSC5) was shown to be a novel GSV protein that underwent a 3.7-fold increase in abundance at the plasma membrane in response to insulin. siRNA-mediated knockdown of TUSC5 decreased insulin-stimulated glucose uptake, although overexpression of TUSC5 had the opposite effect, implicating TUSC5 as a positive regulator of insulin-stimulated glucose transport in adipocytes. Incubation of adipocytes with TNFα caused insulin resistance and a concomitant reduction in TUSC5. Consistent with previous studies, peroxisome proliferator-activated receptor (PPAR) γ agonism reversed TNFα-induced insulin resistance. TUSC5 expression was necessary but insufficient for PPARγ-mediated reversal of insulin resistance. These findings functionally link TUSC5 to GLUT4 trafficking, insulin action, insulin resistance, and PPARγ action in the adipocyte. Further studies are required to establish the exact role of TUSC5 in adipocytes.