Plasma membrane overgrowth causes fibrotic collagen accumulation and immune activation in Drosophila adipocytes.
Plasma membrane overgrowth causes fibrotic collagen accumulation and immune activation in Drosophila adipocytes.
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质膜过度生长导致果蝇脂肪细胞纤维化胶原蛋白积累和免疫激活。
DOI：
10.7554/elife.07187
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发表时间：
2015-06-19
期刊：
影响因子：
7.7
通讯作者：
Pastor-Pareja JC
中科院分区：
文献类型：
--
作者：
Zang Y;Wan M;Liu M;Ke H;Ma S;Liu LP;Ni JQ;Pastor-Pareja JC
许多慢性疾病与胶原蛋白和其他基质蛋白的纤维化沉积有关。关于决定特定组织纤维化优先发生的因素知之甚少。在这里，我们表明质膜（PM）过度生长导致果蝇脂肪细胞的细胞周围胶原积累。我们发现，当阻止PM的内吞去除时，由于急剧的皮质扩张，发动蛋白和其他内吞组分的损失导致传出的IV型胶原的细胞周捕获。沉积物也形成在没有负Toll免疫调节剂仙人掌，多余的PM在这种情况下引起的分泌增加。最后，我们发现Toll或内吞缺陷下游的三聚体胶原积累激活了组织损伤反应。我们的工作表明，流量不平衡和PM拓扑结构可能有助于纤维化。它还将纤维化沉积物置于免疫信号传导的下游和上游，与纤维化疾病的慢性特征一致。http://dx.doi.org/10.7554/eLife.07187.001在动物中，所谓的“基底膜”围绕着器官，有助于将某些组织类型锚在一起，并控制哪些分子在它们之间移动。基底膜由各种蛋白质组成，一种称为胶原蛋白IV的大蛋白质是最丰富的成分。IV型胶原蛋白在细胞内产生，并包装成称为囊泡的气泡状隔室。然后这些囊泡与细胞膜融合，将胶原蛋白释放到细胞外的空间中。有时，在从细胞中释放后，胶原蛋白IV形成有害的聚集体，身体难以分解。这种情况被称为纤维化，并可能严重损害器官和组织。Zang，Wan等人现在已经研究了果蝇中的脂肪细胞（也称为脂肪细胞）如何释放胶原蛋白IV。这种苍蝇被广泛用于研究胶原蛋白的产生，因为对它进行基因研究相对容易，并且它以与许多其他物种相同的方式从细胞中释放胶原蛋白。出乎意料的是，观察到控制内吞作用（将物质带入细胞）过程的蛋白质也参与了从细胞释放IV型胶原蛋白的过程。Zang，Wan等人发现，这是因为内吞作用去除了部分细胞膜：如果内吞作用被阻断，那么多余的细胞膜在IV型胶原蛋白分子释放后将其捕获，从而导致纤维化过程中所见的聚集体。然而，人工减少细胞膜的量恢复了正常的胶原蛋白释放。Zang、Wan等人接下来发现，一种名为Toll的途径对于保护苍蝇免受感染非常重要，但也会影响胶原蛋白的释放。当不存在使Toll通路失活的蛋白质时，过多的细胞膜生长并且胶原蛋白IV也形成聚集体。在这两种情况下，Toll激活或缺乏内吞作用，聚集体引发损伤脂肪细胞的反应。更详细地了解这种反应可能有助于开发治疗产生纤维化的疾病的方法。DOI：http://dx.doi.org/10.7554/eLife.07187.002网站
Many chronic diseases are associated with fibrotic deposition of Collagen and other matrix proteins. Little is known about the factors that determine preferential onset of fibrosis in particular tissues. Here we show that plasma membrane (PM) overgrowth causes pericellular Collagen accumulation in Drosophila adipocytes. We found that loss of Dynamin and other endocytic components causes pericellular trapping of outgoing Collagen IV due to dramatic cortex expansion when endocytic removal of PM is prevented. Deposits also form in the absence of negative Toll immune regulator Cactus, excess PM being caused in this case by increased secretion. Finally, we show that trimeric Collagen accumulation, downstream of Toll or endocytic defects, activates a tissue damage response. Our work indicates that traffic imbalances and PM topology may contribute to fibrosis. It also places fibrotic deposits both downstream and upstream of immune signaling, consistent with the chronic character of fibrotic diseases. DOI: http://dx.doi.org/10.7554/eLife.07187.001 In animals, so-called ‘basement membranes’ surround organs and help to both anchor certain tissue types together and control which molecules move between them. The basement membrane is made up of various proteins, and a large protein called Collagen IV is the most abundant component. Collagen IV is made inside cells and packaged into bubble-like compartments called vesicles. These vesicles then merge with the cell membrane, which releases the collagen into the space outside the cell. Sometimes, after it has been released from the cell, Collagen IV forms harmful aggregates that the body finds difficult to break down. This condition is known as fibrosis, and can severely damage organs and tissues. Zang, Wan et al. have now studied how fat cells—also known as adipocytes—in the fruit fly Drosophila melanogaster release Collagen IV. This fly is widely used to study collagen production because it is relatively easy to perform genetic investigations on it, and it releases collagen from its cells in the same way as many other species. Unexpectedly, it was observed that proteins that control a process known as endocytosis—which takes substances into the cell—are also involved in releasing Collagen IV from the cell. Zang, Wan et al. found that this is because endocytosis removes part of the cell membrane: if endocytosis is blocked, then the excess cell membrane traps Collagen IV molecules after they have been released, causing aggregates like those seen during fibrosis. However, artificially decreasing the amount of cell membrane restored normal collagen release. Zang, Wan et al. next found that a pathway called Toll, which is important for protecting flies against infections, can also affect collagen release. When a protein that inactivates the Toll pathway is absent, too much cell membrane grows and Collagen IV forms aggregates as well. In both cases, Toll activation or lack of endocytosis, the aggregates trigger a reaction that damages the adipocytes. Understanding this reaction in more detail could help to develop treatments for conditions that produce fibrosis. DOI: http://dx.doi.org/10.7554/eLife.07187.002