Loss of Hem1 disrupts macrophage function and impacts migration, phagocytosis, and integrin-mediated adhesion.

Autor:	Stahnke S; Department of Cell Biology, Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany., Döring H; Zoological Institute, Technische Universität Braunschweig, Braunschweig, Germany., Kusch C; Institute of Experimental Biomedicine, University Hospital and Rudolf Virchow Center, University of Würzburg, Würzburg, Germany., de Gorter DJJ; Institute of Molecular Cell Biology, Westphalian Wilhelms University Münster WWU, Münster, Germany., Dütting S; Institute of Experimental Biomedicine, University Hospital and Rudolf Virchow Center, University of Würzburg, Würzburg, Germany., Guledani A; Institute of Molecular Cell Biology, Westphalian Wilhelms University Münster WWU, Münster, Germany., Pleines I; Institute of Experimental Biomedicine, University Hospital and Rudolf Virchow Center, University of Würzburg, Würzburg, Germany., Schnoor M; Department for Molecular Biomedicine, Centre for Investigation and Advanced Studies of the National Polytechnic Institute (Cinvestav-IPN), 07360 Mexico City, Mexico., Sixt M; Institute of Science and Technology IST Austria, Klosterneuburg, Austria., Geffers R; Genome Analytics Group, Helmholtz Center for Infection Research HZI, Braunschweig, Germany., Rohde M; Central Facility for Microscopy, Helmholtz Center for Infection Research HZI, Braunschweig, Germany., Müsken M; Central Facility for Microscopy, Helmholtz Center for Infection Research HZI, Braunschweig, Germany., Kage F; Zoological Institute, Technische Universität Braunschweig, Braunschweig, Germany., Steffen A; Department of Cell Biology, Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany., Faix J; Institute for Biophysical Chemistry, Hannover Medical School MHH, 30625 Hannover, Germany., Nieswandt B; Institute of Experimental Biomedicine, University Hospital and Rudolf Virchow Center, University of Würzburg, Würzburg, Germany., Rottner K; Department of Cell Biology, Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany; Zoological Institute, Technische Universität Braunschweig, Braunschweig, Germany., Stradal TEB; Department of Cell Biology, Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany. Electronic address: theresia.stradal@helmholtz-hzi.de.
Jazyk:	angličtina
Zdroj:	Current biology : CB [Curr Biol] 2021 May 24; Vol. 31 (10), pp. 2051-2064.e8. Date of Electronic Publication: 2021 Mar 11.
DOI:	10.1016/j.cub.2021.02.043
Abstrakt:	Hematopoietic-specific protein 1 (Hem1) is an essential subunit of the WAVE regulatory complex (WRC) in immune cells. WRC is crucial for Arp2/3 complex activation and the protrusion of branched actin filament networks. Moreover, Hem1 loss of function in immune cells causes autoimmune diseases in humans. Here, we show that genetic removal of Hem1 in macrophages diminishes frequency and efficacy of phagocytosis as well as phagocytic cup formation in addition to defects in lamellipodial protrusion and migration. Moreover, Hem1-null macrophages displayed strong defects in cell adhesion despite unaltered podosome formation and concomitant extracellular matrix degradation. Specifically, dynamics of both adhesion and de-adhesion as well as concomitant phosphorylation of paxillin and focal adhesion kinase (FAK) were significantly compromised. Accordingly, disruption of WRC function in non-hematopoietic cells coincided with both defects in adhesion turnover and altered FAK and paxillin phosphorylation. Consistently, platelets exhibited reduced adhesion and diminished integrin αIIbβ3 activation upon WRC removal. Interestingly, adhesion phenotypes, but not lamellipodia formation, were partially rescued by small molecule activation of FAK. A full rescue of the phenotype, including lamellipodia formation, required not only the presence of WRCs but also their binding to and activation by Rac. Collectively, our results uncover that WRC impacts on integrin-dependent processes in a FAK-dependent manner, controlling formation and dismantling of adhesions, relevant for properly grabbing onto extracellular surfaces and particles during cell edge expansion, like in migration or phagocytosis. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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