Faculty Opinions recommendation of Proteasomal degradation within endocytic organelles mediates antigen cross-presentation.

During MHC-I-restricted antigen processing, peptides generated by cytosolic proteasomes are translocated by the transporter associated with antigen processing (TAP) into the endoplasmic reticulum, where they bind to newly synthesized MHC-I molecules.Dendritic cells and other cell types can also generate MHC-I complexes with peptides derived from internalized proteins, a process called crosspresentation.Here, we show that active proteasomes within crosspresenting cell phagosomes can generate these peptides.Active proteasomes are detectable within endocytic compartments in mouse bone marrow-derived dendritic cells.In TAP-deficient mouse dendritic cells, cross-presentation is enhanced by the introduction of human b 2 -microglobulin, which increases surface expression of MHC-I and suggests a role for recycling MHC-I molecules.In addition, surface MHC-I can be reduced by proteasome inhibition and stabilized by MHC-I-restricted peptides.This is consistent with constitutive proteasome-dependent but TAP-independent peptide loading in the endocytic pathway.Rab-GTPase mutants that restrain phagosome maturation increase proteasome recruitment and enhance TAP-independent cross-presentation.Thus, phagosomal/endosomal binding of peptides locally generated by proteasomes allows cross-presentation to generate MHC-Ipeptide complexes identical to those produced by conventional antigen processing.