Wun2-mediated integrin recycling promotes apoptotic cell clearance in Drosophila melanogaster
Wun2-mediated integrin recycling promotes apoptotic cell clearance in Drosophila melanogaster
复制标题
Wun2介导的整合素回收促进果蝇凋亡细胞清除
DOI：
10.1038/s41418-022-01039-3
复制
发表时间：
2022-07-15
影响因子：
12.4
通讯作者：
Xiao，Hui
中科院分区：
文献类型：
--
作者：
Gao，Ning;Zheng，Qian;Xiao，Hui
凋亡细胞（AC）清除是一个复杂的过程中，吞噬细胞识别，吞噬和消化AC在生物体发育和组织稳态。受损的红细胞增多症导致发育缺陷和自身免疫性疾病。在本研究中，我们进行了RNA测序，以系统地确定参与吞噬AC的果蝇黑腹巨噬细胞样S2细胞的监管机构，随后有针对性的RNA干扰筛选。Wunen2（Wun2）是哺乳动物脂质磷酸磷酸酶（LPP）的同源物，被认为是体内外红细胞增多症所必需的。然而，白细胞增多症是独立的Wun 2磷酸酶活性。蛋白质组学分析进一步揭示Rab11及其效应子Rip11是Wun2的相互作用伙伴。因此，Wun2与Rip11和Rab11协作以介导吞噬受体βν整联蛋白亚基向质膜的有效再循环。Wun 2的缺失导致βv整联蛋白亚基（Itgbn）进入溶酶体，导致其降解。细胞表面βv整合素亚基的缺乏导致肌动蛋白细胞骨架的异常和紊乱，从而影响巨噬细胞对AC的伪足的形成，从而不能吞噬AC。这项研究的结果提供了一些见解，阐明了吞噬细胞如何协调AC信号，并采取一种精确的机制来维持其细胞膜表面的吞噬受体，以调节吞噬作用。
Apoptotic cell (AC) clearance is a complex process in which phagocytes recognize, engulf, and digest ACs during organismal development and tissue homeostasis. Impaired efferocytosis results in developmental defects and autoimmune diseases. In the current study, we performed RNA-sequencing to systematically identify regulators involved in the phagocytosis of ACs byDrosophila melanogastermacrophage-like S2 cells, followed by targeted RNA interference screening. Wunen2 (Wun2), a homolog of mammalian lipid phosphate phosphatase (LPP), was deemed as required for efferocytosis both in vitro and in vivo. However, efferocytosis was independent of Wun2 phosphatase activity. Proteomic analysis further revealed that Rab11 and its effector Rip11 are interaction partners of Wun2. Therefore, Wun2 collaborates with Rip11 and Rab11 to mediate efficient recycling of the phagocytic receptor βν integrin subunit to the plasma membrane. The loss of Wun2 results in the routing of βv integrin subunit (Itgbn) into lysosomes, leading to its degradation. The deficiency of βv integrin subunit on the cell surface leads to aberrant and disorganized actin cytoskeleton, thereby influencing the formation of macrophage pseudopodia toward ACs and thus failure to engulf them. The findings of this study provide insights that clarify how phagocytes coordinate AC signals and adopt a precise mechanism for the maintenance of engulfment receptors at their cell membrane surface to regulate efferocytosis.