αv Integrins combine with LC3 and atg5 to regulate Toll-like receptor signalling in B cells

Mridu Acharya, Anna Sokolovska, Jenny M. Tam, Kara L. Conway, Caroline Stefani, Fiona Raso, Subhankar Mukhopadhyay, Marianela Feliu, Elahna Paul, John Savill, Richard O. Hynes, Ramnik J. Xavier, Jatin M. Vyas, Lynda M. Stuart and Adam Lacy-Hulbert ()
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Mridu Acharya: Immunology Program, Benaroya Research Institute
Anna Sokolovska: Laboratory of Developmental Immunology, Massachusetts General Hospital/ Harvard Medical School
Jenny M. Tam: Massachusetts General Hospital/ Harvard Medical School
Kara L. Conway: Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital/ Harvard Medical School
Caroline Stefani: Immunology Program, Benaroya Research Institute
Fiona Raso: Immunology Program, Benaroya Research Institute
Subhankar Mukhopadhyay: Microbial Pathogenesis Group, Wellcome Trust Sanger Institute
Marianela Feliu: Laboratory of Developmental Immunology, Massachusetts General Hospital/ Harvard Medical School
Elahna Paul: Laboratory of Developmental Immunology, Massachusetts General Hospital/ Harvard Medical School
John Savill: MRC/University of Edinburgh Centre for Inflammation Research
Richard O. Hynes: Howard Hughes Medical Institute, Koch Institute of Integrated Cancer Biology, Massachusetts Institute for Technology, Cambridge
Ramnik J. Xavier: Massachusetts General Hospital/ Harvard Medical School
Jatin M. Vyas: Massachusetts General Hospital/ Harvard Medical School
Lynda M. Stuart: Immunology Program, Benaroya Research Institute
Adam Lacy-Hulbert: Immunology Program, Benaroya Research Institute

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10917

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