Peptides Are Transported from the Cytosol to the Rough Endoplasmic Reticulum

Insight into the role that peptide transport, the delivery of peptides to the MHC molecule, plays in the cytosolic processing pathway came from studies of cell lines with defects in peptide presentation by class I MHC molecules. One such mutant cell line, called RMA-S, expresses about 5% of the normal levels of class I MHC molecules on its membrane. Although RMA-S cells synthesize normal levels of class I a chains and ^-microglobulin, neither molecule appears on the membrane. A clue to the mutation in the RMA-S cell line was the discovery by A. Townsend and his colleagues that "feeding" these cells peptides restored their level of membrane-associated class I MHC molecules to normal. These investigators suggested that peptides might be required to stabilize the interaction between the class I a chain and p2-microglobulin. The ability to restore expression of class I MHC molecules on the membrane by feeding the cells predigested peptides suggested that the RMA-S cell line might have a defect in peptide transport.

Subsequent experiments showed that the defect in the RMA-S cell line occurs in the protein that transports peptides from the cytoplasm to the RER, where class I molecules are synthesized. When RMA-S cells were transfected with a functional gene encoding the transporter protein, the cells began to express class I molecules on the membrane. The transporter protein, designated TAP (for transporter associated with antigen processing) is a membrane-spanning heterodimer consisting of two proteins: TAP1 and TAP2 (Figure 8-6a). In addition to their multiple transmembrane segments, the TAP1 and TAP2 proteins each have a domain projecting into the lumen of the RER, and an ATP-binding domain that projects into the cytosol. Both TAP1 and TAP2 belong to the family of ATP-binding cassette proteins found in the membranes of many cells, including bacteria; these proteins mediate ATP-dependent transport of amino acids, sugars, ions, and peptides.

Peptides generated in the cytosol by the proteasome are translocated by TAP into the RER by a process that requires the hydrolysis of ATP (Figure 8-6b). TAP has the highest affinity for peptides containing 8-10 amino acids, which is the optimal peptide length for class I MHC binding. In addition, TAP appears to favor peptides with hydrophobic or basic carboxyl-terminal amino acids, the preferred anchor residues for class I MHC molecules. Thus, TAP is optimized to transport peptides that will interact with class I MHC molecules.

The TAP1 and TAP2 genes map within the class II MHC region, adjacent to the LMP2 and LMP7 genes (see Figure 7-15). Both the transporter genes and these LMP genes are polymorphic; that is, different allelic forms of these genes exist within the population. Allelic differences in LMP-me-diated proteolytic cleavage of protein antigens or in the transport of different peptides from the cytosol into the RER may contribute to the observed variation among individuals in their response to different endogenous antigens. TAP deficiencies can lead to a disease syndrome that has aspects of both immunodeficiency and autoimmunity (see Clinical Focus).

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