The Man/GaINAc-4-SO4-Receptor has Multiple Specificities and Functions

Carbohydrate-specific recognition by receptors contributes to a variety of different biological processes. These include: the folding and assembly of glycoproteins in the endoplasmic reticulum (Helenius 1994; Williams 1995; Trombetta and Helenius 1998), transport of glycoproteins to lysosomes (Kornfeld 1990, 1992), control of the circulatory half-life of individual glycoproteins (Drickamer 1991; Baenziger et al. 1992; Drickamer and Taylor 1993), endocytosis (Ashwell and Harford 1982; Drickamer and Taylor 1993), phagocytosis (Stahl and Ezekowitz 1998), cellular recognition during coagulation (McEver and Cummings 1997; Rosenerg et al. 1997), inflammation (Rosen and Bertozzi 1994; McEver et al. 1995; Lowe 1997), and development (Ioffe and Stanley 1994; Metzler et al. 1994; Chui et al. 1997). We recently described the first example of a carbohydrate-specific receptor, the Man/Ga1NAc-4-SO4 receptor (Fiete et al. 1998), that utilizes two distinct regions with different structural motifs to bind completely different carbohydrate structures. Furthermore, different cell types, such as macrophages and hepatic endothelial cells, express forms of the Man/Ga1NAc-4-SO4 receptor that differ with respect to their carbohydrate specificity. Macrophages express a mannose (Man) specific form of the receptor (Man-receptor), while hepatic endothelial cells express an N-acetylgalactosamine-4-SO4 (Ga1NAc-4-SO4) specific form of the receptor (Ga1NAc-4-SO4-receptor; Fiete and Baenziger 1997; Fiete et al. 1997). The regulated expression of different specificities by the Man/GalNAc-4-SO4-receptor indicates that the Man-receptor and the Ga1NAc-4-SO4receptor have different biological functions. Asparagine-linked carbohydrate structures terminating with the sequence SO4-4Ga1NAcβ1,4G1cNAcβ1,2Manα (S4GGnM) are present on highly restricted populations of glycoproteins, including the pituitary glycoprotein hormones LH and TSH (Green and Baenziger 1988a,b; Baenziger and Green 1991; Stockell Hartree and Renwick 1992; Thotakura and Blithe 1995). The synthesis of these sulfated oligosaccharides is protein specific, and is both hormonally and developmentally regulated (S.M. Dharmesh and J.U. Baenziger, unpubl. obs.; Dharmesh and Baenziger 1993; Manzella et al. 1997). Further, recognition of terminal Ga1NAc-4-SO4 on the oligosaccharides of LH by the Ga1NAc-4-SO4-receptor residing in hepatic endothelial cells (Fiete et al. 1991) plays a critical role in vivo by controlling the circulatory half-life of LH at key points during the ovulatory cycle (Baenziger et al. 1992; Baenziger 1996; Manzella et al. 1996). In contrast, recognition of carbohydrates terminating with Man, Fucose (Fuc), or N-acetylglucosamine (G1cNAc) by the Man-receptor, present on terminally differentiated macrophages, is thought to be essential for phagocytosis of pathogens such as yeasts, bacteria, and viruses (Fraser et al. 1998; Stahl and Ezekowitz 1998). Thus, the Man/Ga1NAc-4-SO4-receptor, in the form of the Man-receptor or the GalNAc-4-SO4-receptor, may fulfill distinct roles that reflect its ligand specificity as well as the setting in which it is expressed.