title: αv Integrins combine with LC3 and atg5 to regulate Toll-like receptor signalling in B cells.
abstract: Integrin signalling triggers cytoskeletal rearrangements, including endocytosis and exocytosis of integrins and other membrane proteins. In addition to recycling integrins, this trafficking can also regulate intracellular signalling pathways. Here we describe a role for αv integrins in regulating Toll-like receptor (TLR) signalling by modulating intracellular trafficking. We show that deletion of αv or β3 causes increased B-cell responses to TLR stimulation in vitro, and αv-conditional knockout mice have elevated antibody responses to TLR-ligand-associated antigens. αv regulates TLR signalling by promoting recruitment of the autophagy component LC3 (microtubule-associated proteins 1 light chain 3) to TLR-containing endosomes, which is essential for progression from NF-κB to IRF signalling, and ultimately for traffic to lysosomes where signalling is terminated. Disruption of LC3 recruitment leads to prolonged NF-κB signalling and increased B-cell proliferation and antibody production. This work identifies a previously unrecognized role for αv and the autophagy components LC3 and atg5 in regulating TLR signalling and B-cell immunity.
authors.affiliation: Immunology Program, Benaroya Research Institute, 1201 Ninth Avenue, Seattle, Washington 98101, USA.
authors.forename: Mridu
authors.initials: M
authors.lastname: Acharya
authors.affiliation: Laboratory of Developmental Immunology, Department of Pediatrics, Massachusetts General Hospital/ Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Sokolovska
authors.affiliation: Division of Infectious Disease, Department of Medicine, , Massachusetts General Hospital/ Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, USA.
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Tam
authors.affiliation: Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital/ Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, USA.
authors.forename: Kara L
authors.initials: KL
authors.lastname: Conway
authors.affiliation: Immunology Program, Benaroya Research Institute, 1201 Ninth Avenue, Seattle, Washington 98101, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Stefani
authors.affiliation: Immunology Program, Benaroya Research Institute, 1201 Ninth Avenue, Seattle, Washington 98101, USA.
authors.forename: Fiona
authors.initials: F
authors.lastname: Raso
authors.affiliation: Microbial Pathogenesis Group, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Subhankar
authors.initials: S
authors.lastname: Mukhopadhyay
authors.affiliation: Laboratory of Developmental Immunology, Department of Pediatrics, Massachusetts General Hospital/ Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, USA.
authors.forename: Marianela
authors.initials: M
authors.lastname: Feliu
authors.affiliation: Laboratory of Developmental Immunology, Department of Pediatrics, Massachusetts General Hospital/ Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, USA.
authors.forename: Elahna
authors.initials: E
authors.lastname: Paul
authors.affiliation: MRC/University of Edinburgh Centre for Inflammation Research, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: John
authors.initials: J
authors.lastname: Savill
authors.affiliation: Howard Hughes Medical Institute, Koch Institute of Integrated Cancer Biology, Massachusetts Institute for Technology, Cambridge, 500 Main Street, Cambridge, Massachusetts 02139, USA.
authors.forename: Richard O
authors.initials: RO
authors.lastname: Hynes
authors.affiliation: Division of Infectious Disease, Department of Medicine, , Massachusetts General Hospital/ Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, USA.
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
authors.affiliation: Division of Infectious Disease, Department of Medicine, , Massachusetts General Hospital/ Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, USA.
authors.forename: Jatin M
authors.identifier: http://orcid.org/0000-0002-9985-9565
authors.initials: JM
authors.lastname: Vyas
authors.affiliation: Immunology Program, Benaroya Research Institute, 1201 Ninth Avenue, Seattle, Washington 98101, USA.|Bill and Melinda Gates Foundation, 500 Fifth Avenue N, Seattle, Washington 98109, USA.
authors.forename: Lynda M
authors.initials: LM
authors.lastname: Stuart
authors.affiliation: Immunology Program, Benaroya Research Institute, 1201 Ninth Avenue, Seattle, Washington 98101, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Lacy-Hulbert
mesh_terms: D000818:Animals; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D001402:B-Lymphocytes / Q000276:immunology*; D015153:Blotting, Western; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D066298:In Vitro Techniques; D039564:Integrin alphaV / Q000235:genetics / Q000276:immunology*; D039661:Integrin beta3 / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008869:Microtubule-Associated Proteins / Q000276:immunology*; D021381:Protein Transport / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology*
chemical_list: C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D039564:Integrin alphaV; D039661:Integrin beta3; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D051193:Toll-Like Receptors