title: Distinct roles for talin-1 and kindlin-3 in LFA-1 extension and affinity regulation.
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.
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.
authors.forename: Craig T
authors.initials: CT
authors.lastname: Lefort
authors.forename: Jan
authors.initials: J
authors.lastname: Rossaint
authors.forename: Markus
authors.initials: M
authors.lastname: Moser
authors.forename: Brian G
authors.initials: BG
authors.lastname: Petrich
authors.forename: Alexander
authors.initials: A
authors.lastname: Zarbock
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Monkley
authors.forename: David R
authors.initials: DR
authors.lastname: Critchley
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ginsberg
authors.forename: Reinhard
authors.initials: R
authors.lastname: Fässler
authors.forename: Klaus
authors.initials: K
authors.lastname: Ley
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002448:Cell Adhesion; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000032:analysis; D018922:HL-60 Cells; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D020014:K562 Cells; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry / Q000378:metabolism*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D009504:Neutrophils / Q000378:metabolism*; D010538:Peritonitis / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D011828:Radiation Chimera; D013047:Specific Pathogen-Free Organisms; D016608:Talin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
chemical_list: D003598:Cytoskeletal Proteins; C477322:FERMT3 protein, human; C090509:Icam1 protein, mouse; D016169:Lymphocyte Function-Associated Antigen-1; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; C518832:TLN1 protein, human; D016608:Talin; C527818:kindlin-3 protein, mouse; C496077:Tln1 protein, mouse; D018799:Intercellular Adhesion Molecule-1; D049452:Green Fluorescent Proteins