Lysophosphatidic acid controls autotaxin binding to β1-integrin : impact on disease progression in murine collagen-induced arthritis

ABSTRACT Autotaxin (ATX) is a lysophospholipase D (lysoPLD) serving as both a lysophosphatidic acid (LPA)-producing enzyme and a LPA docking molecule. ATX binds to the cell surface via interaction with adhesive molecules, including β1-integrin, potentially facilitating LPA access to its specific G protein-coupled receptors. However, the precise protein-protein interaction sequences and their biological implications remain unknown. Here, we identify the interaction domains between ATX and β1-integrin and generate specific blocking antibodies allowing to demonstrate that ATX-β1 binding domain involves a cryptic epitope unmasked by LPA docking. In addition, whereas anti-ATX antibodies do not inhibit the lysoPLD activity, immunological neutralization of the ATX-β1 integrin binding site reduces arthritis development in a collagen-induced arthritis model. These findings offer novel insights into the molecular mechanisms governing ATX functions, which, in addition to its enzymatic activity, requires cell surface binding. These findings suggest that ATX binding domains could be targeted for novel therapeutic approaches. Competing Interest Statement The authors have declared no competing interest. Footnotes The revised version of the manuscript consists of an update to the ORCID numbers of several co-authors. No changes have been made to the text or the figures.