El-Mansi, S;
Robinson, CL;
Kostelnik, KB;
McCormack, JJ;
Mitchell, TP;
Lobato-Márquez, D;
Rajeeve, V;
... Nightingale, TD; + view all
(2023)
Proximity proteomics identifies septins and PAK2 as decisive regulators of actomyosin-mediated expulsion of von Willebrand factor.
Blood
, 141
(8)
pp. 930-944.
10.1182/blood.2022017419.
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Abstract
In response to tissue injury, within seconds the ultra-large glycoprotein von Willebrand factor (VWF) is released from endothelial storage organelles (Weibel−Palade bodies) into the lumen of the blood vasculature, where it leads to the recruitment of platelets. The marked size of VWF multimers represents an unprecedented burden on the secretory machinery of endothelial cells (ECs). ECs have evolved mechanisms to overcome this, most notably an actomyosin ring that forms, contracts, and squeezes out its unwieldy cargo. Inhibiting the formation or function of these structures represents a novel therapeutic target for thrombotic pathologies, although characterizing proteins associated with such a dynamic process has been challenging. We have combined APEX2 proximity labeling with an innovative dual loss-of-function screen to identify proteins associated with actomyosin ring function. We show that p21 activated kinase 2 (PAK2) recruits septin hetero-oligomers, a molecular interaction that forms a ring around exocytic sites. This cascade of events controls actomyosin ring function, aiding efficient exocytic release. Genetic or pharmacological inhibition of PAK2 or septins led to inefficient release of VWF and a failure to form platelet-catching strings. This new molecular mechanism offers additional therapeutic targets for the control of thrombotic disease and is highly relevant to other secretory systems that employ exocytic actomyosin machinery.
| Type: | Article |
|---|---|
| Title: | Proximity proteomics identifies septins and PAK2 as decisive regulators of actomyosin-mediated expulsion of von Willebrand factor |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1182/blood.2022017419 |
| Publisher version: | https://doi.org/10.1182/blood.2022017419 |
| Language: | English |
| Additional information: | © 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution- NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved. See: https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode |
| Keywords: | von Willebrand Factor, Actomyosin, Septins, p21-Activated Kinases, Endothelial Cells, Proteomics, Exocytosis, Cytokinesis, Weibel-Palade Bodies |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Lab for Molecular Cell Bio MRC-UCL |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10167688 |
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