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

Nat Commun. 2016 Mar 11;7:10917. doi: 10.1038/ncomms10917.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy
  • Autophagy-Related Protein 5
  • B-Lymphocytes / immunology*
  • Blotting, Western
  • Cell Proliferation
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • In Vitro Techniques
  • Integrin alphaV / genetics
  • Integrin alphaV / immunology*
  • Integrin beta3 / genetics
  • Mice
  • Mice, Knockout
  • Microscopy, Confocal
  • Microtubule-Associated Proteins / immunology*
  • Protein Transport / immunology*
  • Signal Transduction / immunology
  • Toll-Like Receptors / immunology*

Substances

  • Atg5 protein, mouse
  • Autophagy-Related Protein 5
  • Integrin alphaV
  • Integrin beta3
  • Map1lc3b protein, mouse
  • Microtubule-Associated Proteins
  • Toll-Like Receptors