Proteolytic shedding of ST6Gal-I by BACE1 regulates the glycosylation and function of alpha4beta1 integrins.
Differentiation of monocytes into macrophages is accompanied by increased cell adhesiveness, due in part to the activation of alpha4beta1 integrins. Here we report that the sustained alpha4beta1 activation associated with macrophage differentiation results from expression of beta1 integrin subunits that lack alpha2-6-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 beta1 hyposialylation and enhanced alpha4beta1-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, beta1 hyposialylation, and alpha4beta1-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 beta1 subunit. Collectively, these results describe a novel mechanism for alpha4beta1 regulation and further suggest an unanticipated role for BACE1 in macrophage function.
Woodard-Grice
Alencia V
AV
Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
McBrayer
Alexis C
AC
Wakefield
John K
JK
Zhuo
Ya
Y
Bellis
Susan L
SL
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D015703:Antigens, CD / Q000096:biosynthesis*; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D015536:Down-Regulation / Q000502:physiology; D006031:Glycosylation; D006801:Humans; D039041:Integrin alpha4beta1 / Q000378:metabolism*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008264:Macrophages / Q000201:enzymology*; D009000:Monocytes / Q000201:enzymology*; D046188:Protein Modification, Translational / Q000502:physiology*; D021122:Protein Subunits / Q000378:metabolism; D012794:Sialic Acids / Q000378:metabolism; D012799:Sialyltransferases / Q000096:biosynthesis*; D020298:U937 Cells; D015854:Up-Regulation / Q000502:physiology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase
D053829:Amyloid Precursor Protein Secretases; D015703:Antigens, CD; D016282:Aspartic Acid Endopeptidases; D039041:Integrin alpha4beta1; D018950:Lipopolysaccharide Receptors; D021122:Protein Subunits; D012794:Sialic Acids; D012799:Sialyltransferases; D019010:Vascular Cell Adhesion Molecule-1; C093493:ST6GAL1 protein, human; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase; C509280:BACE1 protein, human