Sorting Nexin 31 Binds Multiple β Integrin Cytoplasmic Domains and Regulates β1 Integrin Surface Levels and Stability

• SNX17 binding to β1 integrin tails prevents routing of β1 integrins to the lysosome.
• FERM-SNX family member SNX31, but not SNX27, interacts with β integrin tails.
• SNX31 is an endosomal protein highly expressed in bladder and melanoma cells.
• SNX31 increases β1 integrin stability in SNX17-depleted cells.
• SNX31 is an integrin interactor that regulates lysosomal degradation of integrins.

Trafficking of α5β1 integrin to lysosomes and its subsequent degradation is influenced by ligand occupancy and the binding of SNX17 via its protein 4.1, ezrin, radixin, moesin (FERM) domain to the membrane-distal NPxY motif in the cytoplasmic domain of β1 integrin in early endosomes. Two other sorting nexin (SNX) family members, namely SNX27 and SNX31, share with SNX17 next to their obligate phox domain a FERM domain, which may enable them to bind β integrin tails. Here we report that, in addition to SNX17, SNX31 but not SNX27 binds several β integrin tails in early endosomes in a PI3 (phosphatidylinositide 3)-kinase-dependent manner. Similarly like SNX17, binding of SNX31 with β1 integrin tails in early endosomes occurs between the FERM domain and the membrane-distal NPxY motif in the β1 integrin cytoplasmic domain. Furthermore, expression of SNX31 rescues β1 integrin surface levels and stability in SNX17-depleted cells. In contrast to SNX17, expression of SNX31 is restricted and found highly expressed in bladder and melanoma tissue. Altogether, these results demonstrate that SNX31 is an endosomal regulator of β integrins with a restricted expression pattern.

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