Arhgef6 (alpha-PIX) cytoskeletal regulator signals to GTPases and Cofilin to couple T cell migration speed and persistence.

Autor: Mamula D; Institute for Biochemistry and Cell Biology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.; Present address: Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden., Korthals M; Institute for Biochemistry and Cell Biology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany., Hradsky J; Institute for Biochemistry and Cell Biology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany., Gottfried A; Institute for Biochemistry and Cell Biology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany., Fischer KD; Institute for Biochemistry and Cell Biology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.; Center for Cellular Imaging and Innovative Disease Models, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany., Tedford K; Institute for Biochemistry and Cell Biology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.; Center for Cellular Imaging and Innovative Disease Models, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
Jazyk: angličtina
Zdroj: Journal of leukocyte biology [J Leukoc Biol] 2021 Nov; Vol. 110 (5), pp. 839-852. Date of Electronic Publication: 2021 Feb 02.
DOI: 10.1002/JLB.1A1219-719R
Abstrakt: Immunity is governed by successful T cell migration, optimized to enable a T cell to fully scan its environment without wasted movement by balancing speed and turning. Here we report that the Arhgef6 RhoGEF (aka alpha-PIX; αPIX; Cool-2), an activator of small GTPases, is required to restrain cell migration speed and cell turning during spontaneous migration on 2D surfaces. In Arhgef6 -/- T cells, expression of Arhgef7 (beta-PIX; βPIX; Cool-1), a homolog of Arhgef6, was increased and correlated with defective activation and localization of Rac1 and CDC42 GTPases, respectively. Downstream of Arhgef6, PAK2 (p21-activated kinase 2) and LIMK1 phosphorylation was reduced, leading to increased activation of Cofilin, the actin-severing factor. Consistent with defects in these signaling pathways, Arhgef6 -/- T cells displayed abnormal bilobed lamellipodia and migrated faster, turned more, and arrested less than wild-type (WT) T cells. Using pharmacologic inhibition of LIMK1 (LIM domain kinase 1) to induce Cofilin activation in WT T cells, we observed increased migration speed but not increased cell turning. In contrast, inhibition of Cdc42 increased cell turning but not speed. These results suggested that the increased speed of the Arhgef6 -/- T cells is due to hyperactive Cofilin while the increased turning may be due to abnormal GTPase activation and recruitment. Together, these findings reveal that Arhgef6 acts as a repressor of T cell speed and turning by limiting actin polymerization and lamellipodia formation.
(©2021 The Authors. Journal of Leukocyte Biology published by Wiley Periodicals LLC on behalf of Society for Leukocyte Biology.)
Databáze: MEDLINE
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