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Dev Cell. 2019 Mar 23. pii: S1534-5807(19)30146-7. doi: 10.1016/j.devcel.2019.02.023. [Epub ahead of print]

Leukocyte Cytoskeleton Polarization Is Initiated by Plasma Membrane Curvature from Cell Attachment.

Author information

1
Department of Pharmacology, Vascular Biology and Therapeutic Program, Yale University, New Haven, CT 06520, USA.
2
Department of Cellular and Molecular Physiology, Yale University, New Haven, CT 06520, USA; Nanobiology Institute, Yale University, New Haven, CT 06520, USA; Department of Molecular Biophysics and Biochemistry, Yale School of Medicine, Yale University, New Haven, CT 06520, USA.
3
Department of Geriatrics, the First affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
4
Snyder Institute for Chronic Diseases Mouse Phenomics Resource Laboratory, University of Calgary, Calgary AB T2N 4N1, Canada; Department of Microbiology, Immunology, and Infectious Diseases, University of Calgary, Calgary AB T2N 4N1, Canada.
5
Department of Internal Medicine, Yale University, New Haven, CT 06520, USA.
6
Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA.
7
The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 5290002, Israel.
8
Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences (CAS), Shanghai, China.
9
Snyder Institute for Chronic Diseases Mouse Phenomics Resource Laboratory, University of Calgary, Calgary AB T2N 4N1, Canada; Department of Physiology and Pharmacology, Cumming School of Medicine, and Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary AB T2N 4N1, Canada.
10
Department of Genetics, Yale University, New Haven, CT 06520, USA.
11
Department of Neuroscience, Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10025, USA.
12
Department of Cellular and Molecular Physiology, Yale University, New Haven, CT 06520, USA; Nanobiology Institute, Yale University, New Haven, CT 06520, USA; Department of Molecular Biophysics and Biochemistry, Yale School of Medicine, Yale University, New Haven, CT 06520, USA; Centre National de la Recherche Scientifique (CNRS), Paris, France. Electronic address: erdem.karatekin@yale.edu.
13
Department of Pharmacology, Vascular Biology and Therapeutic Program, Yale University, New Haven, CT 06520, USA. Electronic address: wenwen.tang@yale.edu.
14
Department of Pharmacology, Vascular Biology and Therapeutic Program, Yale University, New Haven, CT 06520, USA. Electronic address: dan.wu@yale.edu.

Abstract

Cell polarization is important for various biological processes. However, its regulation, particularly initiation, is incompletely understood. Here, we investigated mechanisms by which neutrophils break their symmetry and initiate their cytoskeleton polarization from an apolar state in circulation for their extravasation during inflammation. We show here that a local increase in plasma membrane (PM) curvature resulting from cell contact to a surface triggers the initial breakage of the symmetry of an apolar neutrophil and is required for subsequent polarization events induced by chemical stimulation. This local increase in PM curvature recruits SRGAP2 via its F-BAR domain, which in turn activates PI4KA and results in PM PtdIns4P polarization. Polarized PM PtdIns4P is targeted by RPH3A, which directs PIP5K1C90 and subsequent phosphorylated myosin light chain polarization, and this polarization signaling axis regulates neutrophil firm attachment to endothelium. Thus, this study reveals a mechanism for the initiation of cell cytoskeleton polarization.

KEYWORDS:

BAR domain; SRGAP2; adhesion; cell polarization; neutrophil; phosphatidylinositol-4-phosphate

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