Functional Significance of Glycoprotein Clearance by the Asialoglycoprotein Receptor and the Mannose/GalNAc-4-SO4 Receptor

Glycosylation plays an important role in many biological functions. Two highly abundant, carbohydrate-specific, endocytic receptors reside in parenchymal and endothelial cells of the liver. Our lab has shown that the asialoglycoprotein receptor: ASGR) is capable of clearing glycoproteins bearing terminal Siaalpha2,6GalNAc as well as ones bearing terminal Gal/ GalNAc and that the Mannose/GalNAc-4-SO4 receptor: MR) is capable of clearing glycoproteins bearing terminal GalNAc-4-SO4. I am taking a genetic approach identifying endogenous ligands for the ASGR and the MR in vivo and establishing the biologic significance of clearing these glycoproteins from the blood. A number of glycosylated hormones such as luteinizing hormone: LH), thyroid stimulating hormone, and the prolactin like proteins bear structures that would be recognized by either the ASGR or the MR and clearance would potentially help regulate their concentrations following release into the blood. I have obtained ASGR-/-, MR-/-, and ASGR-/-MR-/- mice. I am using mass spectrometric methods to identify glycoproteins that are elevated in the blood of these mice. Glycoproteins bearing Siaalpha2,6Gal are elevated in ASGR-/- mice suggesting that glycoproteins with Siaalpha2,6Gal rather than terminal Gal or GalNAc are cleared by the ASGR. Many are acute phase proteins and we propose that the ASGR helps regulate their relative concentrations in vivo and enhances their increase during the acute phase response. LH bears terminal GalNAc-4-SO4 and the half life of LH is increased in MR-/- mice indicating that the MR does account for LH clearance in vivo. ASGR-/- mice also have elevated LH, but the half life is not increased indicating an alternative mechanism of elevating LH in ASGR-/-, likely through a protein bearing Siaalpha2,6Gal/GalNAc. Ablation of both the MR and ASGR results in mice that are fertile, but unable to induce parturition. This suggests clearance of proteins bearing Siaalpha2,6Gal/GalNAc and GalNAc-4-SO4 is critical for appropriate plasma protein levels changes associated with parturition. Clearance by the ASGR and MR may contribute to regulating the concentrations of a range of glycoproteins including acute phase proteins and hormones