Hyposialylation Regulates α4β1 Integrin Binding to VCAM‐1

Monocyte activation and differentiation is accompanied by enhanced α4β1 integrin activity, which promotes extravasation and migration through inflamed tissues. We report that PMA treatment of U937 cells induces rapid, yet transient, activation of α4β1 receptors, followed by a more pronounced and sustained increase in α4β1 binding activity. Our results suggest that this latter adhesive phase results from the expression of β1 integrin subunits that lack α2–6 sialic acids. During differentiation of both U937 cells and primary CD14+ human monocytes, the ST6Gal‐I sialyltransferase is downregulated, leading to β1 hyposialylation. Importantly, ST6Gal‐I downregulation results from cleavage by BACE1, which we show is dramatically upregulated during macrophage differentiation. BACE1 upregulation, ST6Gal‐I shedding, β1 hyposialylation and α4β1–dependent VCAM‐1 binding are temporally correlated, and share the same signaling mechanism (PKC/ras/ERK). Preventing ST6Gal‐I downregulation, through both BACE1 inhibition and constitutive overexpression of ST6Gal‐I, eliminates VCAM‐1 binding. Similarly, preventing hyposialylation inhibits a differentiation‐induced change in β1 conformation into a more activated state. Collectively these results describe a novel mechanism for α4β1 regulation, and further suggest an unanticipated role for BACE1 in macrophage function.