title: Zyxin regulates endothelial von Willebrand factor secretion by reorganizing actin filaments around exocytic granules.
abstract: Endothelial exocytosis of Weibel-Palade body (WPB) is one of the first lines of defence against vascular injury. However, the mechanisms that control WPB exocytosis in the final stages (including the docking, priming and fusion of granules) are poorly understood. Here we show that the focal adhesion protein zyxin is crucial in this process. Zyxin downregulation inhibits the secretion of von Willebrand factor (VWF), the most abundant cargo in WPBs, from human primary endothelial cells (ECs) induced by cAMP agonists. Zyxin-deficient mice exhibit impaired epinephrine-stimulated VWF release, prolonged bleeding time and thrombosis, largely due to defective endothelial secretion of VWF. Using live-cell super-resolution microscopy, we visualize previously unappreciated reorganization of pre-existing actin filaments around WPBs before fusion, dependent on zyxin and an interaction with the actin crosslinker α-actinin. Our findings identify zyxin as a physiological regulator of endothelial exocytosis through reorganizing local actin network in the final stage of exocytosis.
authors.affiliation: Laboratory of Vascular Biology, Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing 100871, China.
authors.forename: Xiaofan
authors.initials: X
authors.lastname: Han
authors.affiliation: Laboratory of Vascular Biology, Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing 100871, China.
authors.forename: Pin
authors.initials: P
authors.lastname: Li
authors.affiliation: Laboratory of Vascular Biology, Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing 100871, China.
authors.forename: Zhenghao
authors.initials: Z
authors.lastname: Yang
authors.affiliation: The State Key Laboratory of Biomembrane and Membrane Biotechnology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Laboratory of Institute of Molecular Medicine, Peking University, Beijing 100871, China.
authors.forename: Xiaoshuai
authors.initials: X
authors.lastname: Huang
authors.affiliation: Laboratory of Vascular Biology, Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing 100871, China.
authors.forename: Guoqin
authors.initials: G
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Laboratory of Vascular Biology, Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing 100871, China.
authors.forename: Xuya
authors.initials: X
authors.lastname: Kang
authors.affiliation: Laboratory of Vascular Biology, Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing 100871, China.
authors.forename: Xueting
authors.initials: X
authors.lastname: Hu
authors.affiliation: Laboratory of Vascular Biology, Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing 100871, China.
authors.forename: Qiuping
authors.initials: Q
authors.lastname: Deng
authors.affiliation: The State Key Laboratory of Biomembrane and Membrane Biotechnology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Laboratory of Institute of Molecular Medicine, Peking University, Beijing 100871, China.
authors.forename: Liangyi
authors.initials: L
authors.lastname: Chen
authors.affiliation: The State Key Laboratory of Biomembrane and Membrane Biotechnology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Laboratory of Institute of Molecular Medicine, Peking University, Beijing 100871, China.
authors.forename: Aibin
authors.initials: A
authors.lastname: He
authors.affiliation: Laboratory of Vascular Biology, Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing 100871, China.
authors.forename: Yingqing
authors.initials: Y
authors.lastname: Huo
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia 20147, USA.|National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Li
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia 20147, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Betzig
authors.affiliation: Laboratory of Vascular Biology, Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing 100871, China.
authors.forename: Jincai
authors.initials: J
authors.lastname: Luo
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000185:Actinin / Q000378:metabolism; D000818:Animals; D001760:Bleeding Time; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000819:agonists; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004837:Epinephrine / Q000494:pharmacology; D005089:Exocytosis / Q000187:drug effects / Q000502:physiology*; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D000069416:Intravital Microscopy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000378:metabolism; D013927:Thrombosis / Q000473:pathology; D020302:Weibel-Palade Bodies / Q000378:metabolism; D060589:Zyxin / Q000502:physiology*; D014841:von Willebrand Factor / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; C092842:ZYX protein, human; C498285:Zyx protein, mouse; D060589:Zyxin; D014841:von Willebrand Factor; D000185:Actinin; D005576:Colforsin; D000242:Cyclic AMP; D004837:Epinephrine