Classical class I molecules assemble in the endoplasmic reticulum (ER)
with peptides mostly generated from cytosolic proteins by the proteas
ome. The activity of the proteasome can be modulated by a variety of a
ccessory protein complexes. A subset of the proteasome beta-subunits (
LMP2, LMP7, and MECL-1) and one of the accessory complexes, PA28, are
upregulated by gamma-interferon and affect the generation of peptides
to promote more efficient antigen recognition. The peptides are transl
ocated into the ER by the transporter associated with antigen processi
ng (TAP). A transient complex containing a class I heavy chain-beta(2)
microglobulin (beta(2)m) dimer is assembled onto the TAP molecule by
successive interactions with the ER chaperones calnexin and calreticul
in and a specialized molecule, tapasin. Peptide binding releases the c
lass I-beta(2)m dimer for transport to the cell surface, while lack of
binding results in proteasome-mediated degradation. The products of c
ertain nonclassical MHC-linked class I genes bind peptides in a simila
r way. A homologous set of beta(2)m-associated membrane glycoproteins,
the CD1 molecules, appears to bind lipid-based ligands within the end
ocytic pathway.