The Drosophila chemokine-like Orion bridges phosphatidylserine and Draper in phagocytosis of neurons.
The Drosophila chemokine-like Orion bridges phosphatidylserine and Draper in phagocytosis of neurons.
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DOI：
10.1073/pnas.2303392120
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发表时间：
2023-06-13
影响因子：
11.1
通讯作者：
Han, Chun
中科院分区：
文献类型：
--
作者：
Ji, Hui;Wang, Bei;Shen, Yifan;Labib, David;Lei, Joyce;Chen, Xinchen;Sapar, Maria;Boulanger, Ana;Dura, Jean-Maurice;Han, Chun
吞噬细胞通过吞噬患病或受损的神经元分支而有效地清除它们，同时保持健康的分支不受影响。吞噬细胞如何识别退化的神经突仍然知之甚少。在这里，我们确定了一个关键作用的分泌蛋白猎户座在检测和吞噬果蝇的退化神经突。使用树突变性的多种模型，我们发现Orion作为神经元“吃我”信号磷脂酰丝氨酸（PS）和吞噬细胞上的吞噬受体德雷珀之间的桥接分子，使吞噬作用。我们的研究揭示了PS介导的体内吞噬作用中缺失的一环，揭示了决定吞噬细胞敏感性的因素，并暗示了操纵神经退行性疾病中神经元“吃我”信号检测的潜力。变性神经元的吞噬清除由暴露在神经元表面上的“吃我”信号触发。果蝇中保守的神经元eat-me信号磷脂酰丝氨酸（PS）和吞噬受体德雷珀（Drpr）介导变性神经元的吞噬作用。然而，PS是如何识别的Drpr表达的吞噬细胞在体内仍然知之甚少。使用多个模型的树突变性，我们表明，果蝇趋化因子样蛋白猎户座可以结合到PS，并负责检测PS暴露在神经元上，它是提供细胞非自主涂层PS暴露树突和介导PS和Drpr之间的相互作用，从而使吞噬作用。因此，Orion在神经元和吞噬细胞上的积累分别通过增强和抑制吞噬作用产生相反的结果。此外，Orion剂量是吞噬细胞对暴露在神经元上的PS的敏感性的关键决定因素。最后，诱变分析表明，Orion和人类免疫调节蛋白之间共享的序列基序对Orion功能很重要。因此，我们的研究结果揭示了在果蝇PS介导的吞噬作用中缺失的一环，并暗示了神经元吞噬作用的保守机制。
Phagocytes efficiently clear sick or damaged neuronal branches by engulfing them, while leaving healthy branches untouched. How phagocytes recognize degenerating neurites remains poorly understood. Here, we identified a key role for the secreted protein Orion in the detection and engulfment of degenerating neurites in Drosophila. Using multiple models of dendrite degeneration, we found that Orion acts as a bridging molecule between the neuronal “eat-me” signal phosphatidylserine (PS) and the engulfment receptor Draper on phagocytes, enabling phagocytosis. Our study reveals a missing link in PS-mediated phagocytosis in vivo, sheds light on factors determining the sensitivity of phagocytes, and implies the potential for manipulating the detection of neuronal “eat-me” signals in neurodegenerative diseases. Phagocytic clearance of degenerating neurons is triggered by “eat-me” signals exposed on the neuronal surface. The conserved neuronal eat-me signal phosphatidylserine (PS) and the engulfment receptor Draper (Drpr) mediate phagocytosis of degenerating neurons in Drosophila. However, how PS is recognized by Drpr-expressing phagocytes in vivo remains poorly understood. Using multiple models of dendrite degeneration, we show that the Drosophila chemokine–like protein Orion can bind to PS and is responsible for detecting PS exposure on neurons; it is supplied cell-non-autonomously to coat PS-exposing dendrites and to mediate interactions between PS and Drpr, thus enabling phagocytosis. As a result, the accumulation of Orion on neurons and on phagocytes produces opposite outcomes by potentiating and suppressing phagocytosis, respectively. Moreover, the Orion dosage is a key determinant of the sensitivity of phagocytes to PS exposed on neurons. Lastly, mutagenesis analyses show that the sequence motifs shared between Orion and human immunomodulatory proteins are important for Orion function. Thus, our results uncover a missing link in PS-mediated phagocytosis in Drosophila and imply conserved mechanisms of phagocytosis of neurons.
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DOI：
10.1073/pnas.2111818119
发表时间：
2022-01-25
影响因子：
11.1
作者：
Ji H;Sapar ML;Sarkar A;Wang B;Han C
通讯作者：
Han C
改进的荧光蛋白用于内源性蛋白质标记。
影响因子：
16.6
作者：
Feng S;Sekine S;Pessino V;Li H;Leonetti MD;Huang B
通讯作者：
Huang B
影响因子：
11.4
作者：
Li, Tao;Chiou, Brian;Piao, Xianhua
通讯作者：
Piao, Xianhua
影响因子：
16.2
作者：
Awasaki, T;Tatsumi, R;Ito, K
通讯作者：
Ito, K
影响因子：
2.9
作者：
Andersen, MH;Graversen, H;Rasmussen, JT
通讯作者：
Rasmussen, JT