Erap

Chaperone

FIGURE 6-16 The class I MHC pathway of antigen presentation. The stages in the processing of cytosolic proteins are described in the text. ERAP, endoplasmic reticulum associated peptidase; ER, endoplasmic reticulum; p2m, ^-microglobulin; TAP, transporter associated with antigen processing; Ub, ubiquitin.

so that the peptides produced usually contain carboxyl-terminal hydrophobic amino acids such as leucine, valine, isoleucine, and methionine or basic residues such as lysine or arginine. These kinds of C termini are typical of peptides that are transported into the class I pathway and bind to class I molecules. This is one mechanism by which IFN-y enhances antigen presentation, another mechanism being increased expression of MHC molecules (see Fig. 6-9). Thus, proteasomes are excellent examples of organelles whose basic cellular function has been adapted for a specialized role in antigen presentation.

Some protein antigens apparently do not require ubiq-uitination or proteasomes to be presented by the class I MHC pathway and are presumably degraded by cytosolic proteases. In addition, the signal sequences of membrane and secreted proteins are usually cleaved by signal pep-tidase and degraded proteolytically soon after synthesis and translocation into the ER. This ER processing generates class I-binding peptides without a need for proteoly-sis in the cytosol.

Transport of Peptides from the Cytosol to the Endoplasmic Reticulum

Peptides generated in the cytosol are translocated by a specialized transporter into the ER, where newly synthesized class I MHC molecules are available to bind the peptides. Because antigenic peptides for the class I pathway are generated in the cytosol but class I MHC molecules are synthesized in the ER, a mechanism is needed to deliver cytosolic peptides into the ER. This transport is mediated by a dimeric protein called transporter associated with antigen processing (TAP), which is homologous to the ABC transporter family of proteins that mediate ATP-dependent transport of low-molecular-weight compounds across cellular membranes. The TAP protein is located in the ER membrane, where it mediates the active, ATP-dependent transport of peptides from the cytosol into the ER lumen. Although the TAP heterodi-mer has a broad range of specificities, it optimally transports peptides ranging from 8 to 16 amino acids in length and containing carboxyl termini that are basic (in humans) or hydrophobic (in humans and mice). As mentioned before, these are the characteristics of the peptides that are generated in the proteasome and are able to bind to class I MHC molecules.

On the luminal side of the ER membrane, the TAP protein associates with a protein called tapasin, which also has an affinity for newly synthesized empty class I MHC molecules. Tapasin thus brings the TAP transporter into a complex with the class I MHC molecules that are awaiting the arrival of peptides.

Assembly of Peptide-Class I MHC Complexes in the Endoplasmic Reticulum

Peptides translocated into the ER bind to class I MHC molecules that are associated with the TAP dimer through tapasin. The synthesis and assembly of class I molecules involve a multistep process in which peptide binding plays a key role. Class I a chains and p2-microglobulin are synthesized in the ER. Appropriate folding of the nascent a chains is assisted by chaperone proteins, such as the membrane chaperone calnexin and the luminal chaperone calreticulin. Within the ER, the newly formed empty class I dimers remain linked to the TAP complex. Empty class I MHC molecules, tapasin, and TAP are part of a larger peptide-loading complex in the ER that also

Uptake of extracellular proteins into vesicular compartments of APC

Processing of internalized proteins in endosomal/ lysosomal vesicles

Biosynthesis and transport of class II MHC molecules to endosomes

Association of processed peptides with class II MHC molecules in vesicles

Expression of peptide-MHC complexes on cell surface

Protein antigen

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