Cellular Signaling and Production of Galactose-Deficient IgA1 in IgA Nephropathy, an Autoimmune Disease

Figure 2

Pathways of IgA1 O-glycosylation. The hinge region of IgA1 is O-glycosylated in the Golgi apparatus, a structure composed of multiple layers compacted together, with three designated regions: cis, medial, and trans. These structures support differential localization of various glycosyltransferases, an arrangement that confers a level of specificity and order of addition of sugar moieties. Path I shows normal (in healthy controls; HC) sequential addition of N-acetylgalactosamine (GalNAc), galactose (Gal), and N-acetylneuraminic acid (NeuAc) by their respective enzymes, GalNAc-transferase, core 1 galactosyltransferase (C1GalT1), and sialyltransferases, ST6GalNAc-II (adds NeuAc to GalNAc) and/or ST3Gal (adds NeuAc to Gal). There are multiple GalNAc-transferases that can initiate IgA1 O-glycosylation. Path II shows a possible deviation in the localization of ST6GalNAc-II that could lead to a galactose deficiency due to premature sialylation of GalNAc. The addition of sialic acid blocks a later addition of galactose. Path III shows a scenario in which a reduced expression of C1GalT1 in IgA1-secreting cells from IgAN patients would decrease the addition of galactose to IgA1. Pathways II and III represent possible deviations from normal glycosylation that could lead to production of galactose-deficient IgA1. The polymeric form of IgA1 is formed after exit of IgA1 from the Golgi apparatus through the addition of J chain that binds covalently to the tail pieces of the heavy chains. The resultant polymeric IgA1 may be a dimer or higher oligomer.