Antibodies as a model system for protein secretion

Like all proteins destined to be synthesized in the ER, immunoglobulins are characterized by an N-terminal stretch of hydrophobic amino acids, the signal (leader) sequence, first inferred by Milstein and coworkers in 1972 in studies on immunoglobulin (Ig) light chain secretion. The signal sequence interacts with a multimeric ribonucleoprotein, the signal recognition particle (SRP). This interaction arrests translation until the complex formed by ribosome, nascent protein and SRP binds to the SRP receptor or docking protein on the ER membrane. Translocation of the nascent chain across the ER membrane occurs cotranslationally and the signal sequence is then cleaved by specific proteases located on the luminal face of the ER membrane. The first steps of N-linked glycosylation also occur cotranslationally (Figure 1).

The signal sequence is a paradigmatic example of 'positive' sorting: only the proteins that express it enter the secretory pathway. However, not all proteins synthesized within the ER will reach the extracellular space: some of them accumulate in the ER, some in the Golgi. Specific C-terminal sequences have been shown to cause retention within the ER of the proteins possessing them. This has led to the proposal of the bulk flow model, according to which all proteins in the secretory compartment will be secreted 'by default' unless they are marked with specific 'retention signals' which block them within a given organelle.

Protein secretion may be constitutive or regulated. Antibodies are secreted by plasma cells through the constitutive pathway. In the regulated pathway, pro

Figure 1 Assembly and secretion of immunoglobulins. The N-terminal signal sequence (ss) is recognized by the signal recognition particle (srp) on cytosolic nascent proteins. This interaction causes an arrest in translation (-). The complex binds to the srp receptor (or docking protein, srp-r), targeting the ribosome to the ER membrane, and allowing elongation of the nascent polypeptide (+). Translocation of the ER membrane and the first steps of N-linked glycosylation (addition of the GlcNac2Man9Glu3 precursor) occur cotranslationally. Folding and assembly begin when the nascent H and L chains are still on the polysome, and are rapidly completed under the assistance of ER chaperones and folding enzymes (BiP, calnexin, PDI, ERp72, etc.). Only fully assembled molecules are transported to the Golgi, where they undergo terminal processing of their sugar moieties (*) before being released into the extracellular space. Folding and assembly intermediates are retained in the ER, or retrieved in this organelle from the early compartments of the cis Golgi network. A proteolytic system, independent from that of lysosomes, maintains homeostasis in the ER. All transport steps occur within membrane-sealed vesicles that are thought to bud from one compartment and fuse with the next along the exocytic pathway.

Figure 1 Assembly and secretion of immunoglobulins. The N-terminal signal sequence (ss) is recognized by the signal recognition particle (srp) on cytosolic nascent proteins. This interaction causes an arrest in translation (-). The complex binds to the srp receptor (or docking protein, srp-r), targeting the ribosome to the ER membrane, and allowing elongation of the nascent polypeptide (+). Translocation of the ER membrane and the first steps of N-linked glycosylation (addition of the GlcNac2Man9Glu3 precursor) occur cotranslationally. Folding and assembly begin when the nascent H and L chains are still on the polysome, and are rapidly completed under the assistance of ER chaperones and folding enzymes (BiP, calnexin, PDI, ERp72, etc.). Only fully assembled molecules are transported to the Golgi, where they undergo terminal processing of their sugar moieties (*) before being released into the extracellular space. Folding and assembly intermediates are retained in the ER, or retrieved in this organelle from the early compartments of the cis Golgi network. A proteolytic system, independent from that of lysosomes, maintains homeostasis in the ER. All transport steps occur within membrane-sealed vesicles that are thought to bud from one compartment and fuse with the next along the exocytic pathway.

teins are concentrated within intracellular stores (secretory granules) and bursts of secretion can be triggered at rates much higher than the synthetic one. In constitutive secretion there is normally little intracellular accumulation, and secretion depends largely on the rate of synthesis. However, lgM antibodies are an exception to this scheme as their secretion is developmentally regulated (see below). Constitutive secretion is common to virtually all cells, although at different levels. Like most cells specialized in secretion, plasma cells have abundant ER and a developed Golgi apparatus. By contrast, B cells have a very scarce ER.

Secreted proteins are remarkably uniform, and only fully assembled molecules are released extra-cellularly. This selectivity implies the existence of quality control steps in protein synthesis, folding and assembly, which appear to be coupled to intracellular transport. In addition, to maintain cellular homeostasis, proteins which fail these editing steps, and are hence not transported, must be degraded. Antibodies are an excellent model for understanding how cells manage to obtain high secretion efficiency and stringent quality control of the released products. This will be of interest in the general context of protein secretion, as well as for some more specific problems, namely how the onset, duration and intensity of the antibody responses are controlled.

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