Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853.
Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853.
Proc Natl Acad Sci U S A. 2023 Jun 13;120(24):e2303392120. doi: 10.1073/pnas.2303392120. Epub 2023 Jun 5.
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 . However, how PS is recognized by Drpr-expressing phagocytes in vivo remains poorly understood. Using multiple models of dendrite degeneration, we show that the 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 and imply conserved mechanisms of phagocytosis of neurons.
吞噬细胞通过暴露在神经元表面的“吃我”信号清除退化的神经元。保守的神经元“吃我”信号磷脂酰丝氨酸（PS）和吞噬受体 Draper（Drpr）介导 在 中退化神经元的吞噬作用。然而，PS 如何被 Drpr 表达的吞噬细胞在体内识别仍知之甚少。使用多种树突退化模型，我们表明趋化因子样蛋白 Orion 可以与 PS 结合，负责检测神经元上 PS 的暴露；它非自主供应给暴露 PS 的树突并介导 PS 与 Drpr 之间的相互作用，从而促进吞噬作用。因此，Orion 在神经元和吞噬细胞上的积累通过分别增强和抑制吞噬作用产生相反的结果。此外，Orion 的剂量是吞噬细胞对神经元上暴露的 PS 敏感性的关键决定因素。最后，突变分析表明，Orion 和人类免疫调节蛋白之间共享的序列基序对于 Orion 功能很重要。因此，我们的研究结果揭示了 在 PS 介导的吞噬作用中的缺失环节，并暗示了神经元吞噬作用的保守机制。
