Distinct roles for talin-1 and kindlin-3 in LFA-1 extension and affinity regulation

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2012
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Abstract
In inflammation, neutrophils and other leukocytes roll along the microvascular endothelium before arresting and transmigrating into inflamed tissues. Arrest requires conformational activation of the integrin lymphocyte function-associated antigen-1 (LFA-1). Mutations of the FERMT3 gene encoding kindlin-3 underlie the human immune deficiency known as leukocyte adhesion deficiency-III. Both kindlin-3 and talin-1, another FERM domain-containing cytoskeletal protein, are required for integrin activation, but their individual roles in the induction of specific integrin conformers are unclear. Here, we induce differential LFA-1 activation in neutrophils through engagement of the selectin ligand P-selectin glycoprotein ligand-1 or the chemokine receptor CXCR2. We find that talin-1 is required for inducing LFA-1 extension, which corresponds to intermediate affinity and induces neutrophil slow rolling, whereas both talin-1 and kindlin-3 are required for induction of the high-affinity conformation of LFA-1 with an open headpiece, which results in neutrophil arrest. In vivo, both slow rolling and arrest are defective in talin-1–deficient neutrophils, whereas only arrest is defective in kindlin-3–deficient neutrophils. We conclude that talin-1 and kindlin-3 serve distinct functions in LFA-1 activation.
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ley2012blooddistinct Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Craig T. Lefort, Jan Rossaint, Markus Moser, Brian G. Petrich, Alexander Zarbock, Susan J. Monkley, David R. Critchley, Mark H. Ginsberg, Reinhard Fässler, Klaus Ley
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Journal Blood
Year 2012
DOI
10.1182/blood-2011-08-373118
URL
https://sciprofiles.com/publication/view/744b25fdc70ab329cf078b1f663c8481
Keywords
inflammation neutrophils arrest integrin leukocytes glycoprotein lfa talin kindlin immune deficiency

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