Sorting nexin 17 prevents lysosomal degradation of β1 integrins by binding to the β ₁-integrin tail

Integrin functions are controlled by regulating their affinity for ligand, and by the efficient recycling of intact integrins through endosomes. Here we demonstrate that the Kindlin-binding site in the β ₁-integrin cytoplasmic domain serves as a molecular switch enabling the sequential binding of two FERM-domain-containing proteins in different cellular compartments. When β ₁ integrins are at the plasma membrane, Kindlins control ligand-binding affinity. However, when they are internalized, Kindlins dissociate from integrins and sorting nexin 17 (SNX17) is recruited to free β ₁-integrin tails in early endosomes to prevent β ₁-integrin degradation, leading to their recycling back to the cell surface. Our results identify SNX17 as a β ₁-integrin-tail- binding protein that interacts with the free Kindlin-binding site in endosomes to stabilize β ₁ integrins, resulting in their recycling to the cell surface where they can be reused.