Mammalian O -mannosylation of cadherins and plexins is independent of protein O -mannosyltransferases 1 and 2.

Protein O- mannosylation is found in yeast and metazoans, and a family of conserved orthologous protein O- mannosyltransferases is believed to initiate this important post-translational modification. We recently discovered that the cadherin superfamily carries O- linked mannose ( O -Man) glycans at highly conserved residues in specific extracellular cadherin domains, and it was suggested that the function of E-cadherin was dependent on the O- Man glycans. Deficiencies in enzymes catalyzing O- Man biosynthesis, including the two human protein O- mannosyltransferases, POMT1 and POMT2, underlie a subgroup of congenital muscular dystrophies designated α-dystroglycanopathies, because deficient O- Man glycosylation of α-dystroglycan disrupts laminin interaction with α-dystroglycan and the extracellular matrix. To explore the functions of O- Man glycans on cadherins and protocadherins, we used a combinatorial gene-editing strategy in multiple cell lines to evaluate the role of the two POMTs initiating O- Man glycosylation and the major enzyme elongating O- Man glycans, the protein O- mannose β-1,2- N -acetylglucosaminyltransferase, POMGnT1. Surprisingly, O- mannosylation of cadherins and protocadherins does not require POMT1 and/or POMT2 in contrast to α-dystroglycan, and moreover, the O- Man glycans on cadherins are not elongated. Thus, the classical and evolutionarily conserved POMT O- mannosylation pathway is essentially dedicated to α-dystroglycan and a few other proteins, whereas a novel O- mannosylation process in mammalian cells is predicted to serve the large cadherin superfamily and other proteins.