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Nat Commun. 2018 Oct 15;9(1):4259. doi: 10.1038/s41467-018-06744-7.

A phosphatidylinositol 4,5-bisphosphate redistribution-based sensing mechanism initiates a phagocytosis programing.

Mu L1,2, Tu Z3, Miao L2,4, Ruan H1,2, Kang N1,2, Hei Y2, Chen J1,2, Wei W5, Gong F5, Wang B6, Du Y6, Ma G5, Amerein MW7,8, Xia T9,10, Shi Y11,12,13.

Author information

1
School of Life Sciences, Tsinghua University, Beijing, 100084, China.
2
Institute for Immunology and Department of Basic Medical Sciences, Beijing Key Lab for Immunological Research on Chronic Diseases, School of Medicine; Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, 100084, China.
3
Department of Microbiology, Immunology & Infectious Diseases and Snyder Institute, University of Calgary, Calgary, T2N 4N1, AB, Canada.
4
School of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China.
5
State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, China.
6
Department of Biomedical Engineering, School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University, Beijing, 100084, China.
7
Department of Cell Biology and Anatomy, University of Calgary, Calgary, T2N 4N1, AB, Canada.
8
Snyder Institute of Chronic Diseases, University of Calgary, Calgary, T2N 4N1, AB, Canada.
9
School of Life Sciences, Tsinghua University, Beijing, 100084, China. xiatie@biomed.tsinghua.edu.cn.
10
Institute for Immunology and Department of Basic Medical Sciences, Beijing Key Lab for Immunological Research on Chronic Diseases, School of Medicine; Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, 100084, China. xiatie@biomed.tsinghua.edu.cn.
11
School of Life Sciences, Tsinghua University, Beijing, 100084, China. yanshi@biomed.tsinghua.edu.cn.
12
Institute for Immunology and Department of Basic Medical Sciences, Beijing Key Lab for Immunological Research on Chronic Diseases, School of Medicine; Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, 100084, China. yanshi@biomed.tsinghua.edu.cn.
13
Department of Microbiology, Immunology & Infectious Diseases and Snyder Institute, University of Calgary, Calgary, T2N 4N1, AB, Canada. yanshi@biomed.tsinghua.edu.cn.

Abstract

Phagocytosis is one of the earliest cellular functions, developing approximately 2 billion years ago. Although FcR-based phagocytic signaling is well-studied, how it originated from ancient phagocytosis is unknown. Lipid redistribution upregulates a phagocytic program recapitulating FcR-based phagocytosis with complete dependence on Src family kinases, Syk, and phosphoinositide 3-kinases (PI3K). Here we show that in phagocytes, an atypical ITAM sequence in the ancient membrane anchor protein Moesin transduces signal without receptor activation. Plasma membrane deformation created by solid structure binding generates phosphatidylinositol 4,5-bisphosphate (PIP2) accumulation at the contact site, which binds the Moesin FERM domain and relocalizes Syk to the membrane via the ITAM motif. Phylogenic analysis traces this signaling using PI3K and Syk to 0.8 billion years ago, earlier than immune receptor signaling. The proposed general model of solid structure phagocytosis implies a preexisting lipid redistribution-based activation platform collecting intracellular signaling components for the emergence of immune receptors.

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