Lysophosphatidic acid controls autotaxin binding to 1-integrin: impact on disease progression in murine collagen-induced arthritis.
Emery, M.; Cuero, C. N.; Bouazza, L.; Internicola, C.; Duboeuf, F.; Cerecero-Aguirre, P.; McCarthy, A. A.; Machuca-Gayet, I.; Leblanc, R.; Peyruchaud, O.
Show 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 {beta}1-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 {beta}1-integrin and generate specific blocking antibodies allowing to demonstrate that ATX-{beta}1 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-{beta}1 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.
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