The asialoglycoprotein receptor clears glycoconjugates terminating with sialic acidα2,6GalNAc

Endogenous ligands have not, to date, been identified for the asialoglycoprotein receptor (ASGP-R), which is abundantly expressed by parenchymal cells in the liver of mammals. On the basis of the rapid clearance of BSA bearing multiple chemically coupled sialic acid (Sia)alpha 2,6GalNAcl beta 1,4GIcNAc beta 1,2Man tetrasaccharides (SiaGGnM-BSA) from the circulation, and the ability of the ASGP-R hepatic lectin-1 subunit to bind SiaGGnM-BSA, we previously proposed that glycoproteins modified with structures terminating with Sia alpha 2,6GalNAc may represent previously unrecognized examples of endogenous ligands for this receptor. Here, we have taken a genetic approach using wild-type and ASGP-R-deficient mice to determine that the ASGIP-R in vivo does indeed account for the rapid clearance of glycoconjugates terminating with Sia alpha 2,6GalNAc. We have also determined that the ASGP-R is able to bind core-substituted oligosaccharides with the terminal sequence Sia alpha 2,6Gal beta 1,4GlcNAc but not those with the terminal Sia alpha 2,3Gal beta 1,4GlcNAc. We propose that glycoproteins bearing terminals Sia alpha 2,6GaINAc and Sia alpha 2,6Gal are endogenous ligands for the ASGP-R, and that the ASGP-R helps to regulate the relative concentration of serum glycoproteins bearing alpha 2,6-linked Sia.