Molecular biology and function of secretory component

The human SC gene locus (PIGR) has been assigned to the long arm of chromosome 1 (region q31-q42). This region contains other genes of immunological interest and is involved in a significant number of recombination events. We have detected restriction fragment length polymorphism (RFLP) for the SC gene; Pvu II revealed a two-allele RFI..P with an autosomal codominant inheritance pattern.

Human SC occurs in three molecular forms: as a basolaterally expressed transmembrane protein (-100 kDa) functioning as pig receptor (plgR); as a stabilizing integrated component (-80 kDa) in S-IgA and S-IgM (bound SC); and as an excess of free SC (-80 kDa) in most exocrine fluids (Figure 1). Cell biology studies first substantiated in the rabbit that SC is produced as a transmembrane protein 2530 kDa larger than the secreted form.

Transmembrane SC (plgR) is composed of five homologous extracellular domains, a transmembrane anchor, and a cytoplasmic tail (Figure 2). Proteolytic cleavage near the apical cell membrane releases SC (bound or free) into exocrine secretions. Free SC appears to exhibit eosinophil-activating properties and may block adhesion of Escherichia coli. Such additional functions suggest that SC has originated phylogenetically from the innate defense system.

The five repeating domains of plgR are stabilized by intrachain disulfide bridges and show considerable amino acid homology with several members of the Ig supergene family, particularly with 1g V domains. The full-length receptor characterization obtained by cloning of cDNA from different species has allowed identification of conserved regions and experimental definition of the functionally most important sequences. The cDNA for human plgR first isolated in our laboratory, encodes a rransmem-

Lamina propria

► J chain transmembrane SC (pig receptor)

Figure 1 Schematic representation of various steps involved in the generation of human secretory IgA (top right) and secretory IgM (bottom right) via plgR-mediated epithelial transport of J chain-containing polymeric IgA (IgA-J) and pentameric IgM (IgM-J) secreted by local plasma cells (left). Transmembrane SC is synthesized in the rough endoplasmic reticulum (RER) of secretory epithelial cells and matures by terminal glycosylation (-•) in the Golgi complex. After being sorted through the trans-Golgi network (TGN), it is phosphorylated (O) and expressed as plgR at the basolateral plasma membrane. Endocytosis of ligand-complexed and unoccupied plgR is followed by transcytosis to apical endosomes and finally by cleavage and release of secretory Ig molecules with bound SC as well as excess of free SC at the luminal cell face. However, some basolateral recycling may first take place for unoccupied plgR. During the external translocation, covalent stabilization of the IgA-SC complexes regularly occurs (two disulfide bridges indicated in secretory IgA), whereas free SC in the secretion apparently serves to stabilize the noncovalent IgM-SC complexes (dynamic equilibrium indicated for secretory IgM).

► J chain transmembrane SC (pig receptor)

free or bound SC

Lamina propria

Figure 1 Schematic representation of various steps involved in the generation of human secretory IgA (top right) and secretory IgM (bottom right) via plgR-mediated epithelial transport of J chain-containing polymeric IgA (IgA-J) and pentameric IgM (IgM-J) secreted by local plasma cells (left). Transmembrane SC is synthesized in the rough endoplasmic reticulum (RER) of secretory epithelial cells and matures by terminal glycosylation (-•) in the Golgi complex. After being sorted through the trans-Golgi network (TGN), it is phosphorylated (O) and expressed as plgR at the basolateral plasma membrane. Endocytosis of ligand-complexed and unoccupied plgR is followed by transcytosis to apical endosomes and finally by cleavage and release of secretory Ig molecules with bound SC as well as excess of free SC at the luminal cell face. However, some basolateral recycling may first take place for unoccupied plgR. During the external translocation, covalent stabilization of the IgA-SC complexes regularly occurs (two disulfide bridges indicated in secretory IgA), whereas free SC in the secretion apparently serves to stabilize the noncovalent IgM-SC complexes (dynamic equilibrium indicated for secretory IgM).

Extracellular Intracellular

Extracellular Intracellular

Delineation of determinants for intracellular routing

Eye Piece Graticule Stage Micrometer

binding site

Rapid andocylosis

Figure 2 Schematic depiction of the mature human transmembrane SC or plgR. The position of cysteines participating in disulfide bonds stabilizing the extracellular lg-like domains 1-5 (D1-D5) are indicated. Arrows mark the initial Ig-binding site in D1, the site for secondary covalent plgA bonding in D5, and the cleavage site near the epithelial cell membrane. Glycosylation sites (-•) and disulfide bonds (—S—S—) are also depicted. Putative determinants in the cytoplasmic tail critical for proper cellular routing are delineated on the basis of findings reported for the rabbit plgR, including the phosphorylated serine residue (®) S655 (counterpart to rabbit S664) and the two tyrosine-based endocytosis motifs. The kink-inducing proline in the membrane-spanning segment suggests signal-transducing capacity of the receptor.

Delineation of determinants for intracellular routing binding site

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