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Wun2-mediated integrin recycling promotes apoptotic cell clearance in Drosophila melanogaster

Abstract

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 by Drosophila melanogaster macrophage-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.

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Fig. 1: RNA-sequencing and RNAi screening of candidate genes involved in efferocytosis.
Fig. 2: Macrophages of the wun2 mutant show defective phagocytosis of ACs.
Fig. 3: wun does not affect ACs clearance for macrophages.
Fig. 4: Wun2 catalytic activity is not required for efferocytosis.
Fig. 5: Wun2 interacts with active Rab11 to regulate ACs clearance.
Fig. 6: Wun2 directly interacts with Rip11 and βv integrin subunit to regulate ACs clearance.
Fig. 7: Wun2 protects βv integrin from degradation by sorting the recycling pathway.
Fig. 8: Wun2 is important for F-actin arrangement at the protrusions to envelop ACs.

Data availability

All data are provided in the manuscript and Supplementary files or are available from the corresponding authors upon reasonable request.

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Acknowledgements

We thank the Bloomington Drosophila Stock Center for the Drosophila melanogaster strains. Additionally, we thank Editage (www.editage.cn) for English language editing.

Funding

This study was partially supported by the National Natural Science Foundation Key Project (breeding program) of China (Grant no. 91954114 to HX), National Natural Science Foundation of China (Grant no. 31871387 to HX), National Natural Science Foundation of China Youth Program (Grant no. 31801164 to QZ), the program of Innovative Research Team for the Central Universities (Grant no. GK202001004 to HX), and the Fundamental Research Key Project Funds for the Central Universities (Grant no. GK202007009 to HX).

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HX and NG conceived the study. NG and QZ performed most of the experiments. XWL, YZW, and ZL provided the materials and performed some experiments. HX, NG, and QZ wrote the manuscript.

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Correspondence to Hui Xiao.

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All animal care and experiments were performed according to the “Guide for the Care and Use of Laboratory Animals,” which were approved by the Institutional Animal Care and Use Committee at Shaanxi Normal University, and all manipulations were conducted in accordance with established guidelines.

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Gao, N., Zheng, Q., Wang, Y. et al. Wun2-mediated integrin recycling promotes apoptotic cell clearance in Drosophila melanogaster. Cell Death Differ (2022). https://doi.org/10.1038/s41418-022-01039-3

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