β1,4-galactosyltransferase 1 is a novel receptor for IgA in human mesangial cells

IgA nephropathy is characterized by mesangial deposition of IgA, mesangial cell proliferation, and extracellular matrix production. Mesangial cells bind IgA, but the identity of all potential receptors involved remains incomplete. The transferrin receptor (CD71) acts as a mesangial cell IgA receptor and its expression is upregulated in many forms of glomerulonephritis, including IgA nephropathy. CD71 is not expressed in healthy glomeruli and blocking CD71 does not completely abrogate mesangial cell IgA binding. Previously we showed that mesangial cells express a receptor that binds the Fc portion of IgA and now report that this receptor is an isoform of beta-1,4-galactosyltransferase. A human mesangial cell cDNA library was screened for IgA binding proteins and beta-1,4-galactosyltransferase identified. Cell surface expression of the long isoform of beta-1,4galactosyltransferase was shown by flow cytometry and confocal microscopy and confirmed by immunoblotting. Glomerular beta-1,4-galactosyltransferase expression was increased in IgA nephropathy. IgA binding and IgA-induced mesangial cell phosphorylation of spleen tyrosine kinase and IL-6 synthesis were inhibited by a panel of beta-1,4galactosyltransferase-specific antibodies, suggesting IgA binds to the catalytic domain of beta-1,4-galactosyltransferase. Thus, beta-1,4-galactosyltransferase is a constitutively expressed mesangial cell IgA receptor with an important role in both mesangial IgA clearance and the initial response to IgA deposition.