Antigen cross-presentation: proteasome location, location, location

Abstract

Our understanding of the mechanisms by which peptides from proteins present in phagosomes and endosomes are processed and presented on MHC class I molecules, in a pathway called cross-presentation, is still incomplete. One of the main questions arising from currently proposed models is how do proteins in the phagosome lumen reach the proteasome in the cytoplasm to be processed properly. In this issue of The EMBO Journal, Sengupta et al (2019) present evidence for a surprising turn of events where, in fact, the proteasome acts within the lumen of endosomes and phagosomes.

Figure 1. Models for the location of the proteasome in cross‐presentation

The proteasome can be positioned in various locations within the cell to accommodate the need to process large polypeptides into the smaller peptides that fit best on the groove of MHC I molecules. (1) In the phagosome‐to‐cytosol pathway, large polypeptides are translocated from the lumen into the cytoplasm by an unknown transporter to reach the proteasome. Antigenic peptides enter the ER lumen through the TAP transporters of the classical MHC I pathway. (2) The proteasome is closely associated with the phagosome membrane (in the cytoplasmic side). Large polypeptides translocated as in 1 reach the proteasome and the peptides are moved back into the phagosome lumen through TAP to bind MHC I molecules. (3) The positioning of the proteasome in the phagosome lumen has the advantage to enable a very efficient system to generate peptides binding directly to MHC I molecules in the lumen (acquired through ER–phagosome interaction). This processing pathway, which is more efficient than the potential processing by hydrolases, would take place in a TAP‐independent process.