Proteolytic shedding of ST6Gal-I by BACE1 regulates the glycosylation and function of α4β1 integrins

Differentiation of monocytes into macrophages is accompanied by increased cell adhesiveness, due in part to the activation of alpha 4 beta 1 integrins. Here we report that the sustained alpha 4 beta 1 activation associated with macrophage differentiation results from expression of beta 1 integrin subunits that lack alpha 2-6-linked sialic acids, a carbohydrate modification added by the ST6Gal-I sialyltransferase. During differentiation of U937 monocytic cells and primary human CD14(+) monocytes, ST6Gal-I is down-regulated, leading to beta 1 hyposialylation and enhanced alpha 4 beta 1-dependent VCAM-1 binding. Importantly, ST6Gal-I down-regulation results from cleavage by the BACE1 secretase, which we show is dramatically up-regulated during macrophage differentiation. BACE1 up-regulation, ST6Gal-I shedding, beta 1 hyposialylation, and alpha 4 beta 1-dependent VCAM-1 binding are all temporally correlated and share the same signaling mechanism (protein kinase C/Ras/ERK). Preventing ST6Gal-I down-regulation (and therefore integrin hyposialylation), through BACE1 inhibition or ST6Gal-I constitutive overexpression, eliminates VCAM-1 binding. Similarly, preventing integrin hyposialylation inhibits a differentiation-induced increase in the expression of an activation-dependent conformational epitope on the beta 1 subunit. Collectively, these results describe a novel mechanism for alpha 4 beta 1 regulation and further suggest an unanticipated role for BACE1 in macrophage function.