Asparaginyl endopeptidase: case history of a class II MHC compartment protease

Although the endpoint of the class II antigen-processing pathway is well characterized, the processing events that lead to the production of class II major histocompatibility complex (MHC)/peptide complexes are not. It is generally assumed that protease action on native antigen substrates leads to unfolding and capture of either long or short peptides. Whether specific protease activities are needed for presentation of particular T-cell epitopes is largely unknown. Here, we review our recent studies that aim to identify the processing enzymes that initiate processing of different antigens. We suggest a general strategy that can potentially identify preferred relationships between substrates and processing enzymes in vitro and suggest ways in which these relationships can be tested in vivo. We draw heavily on the example of asparaginyl endopeptidase, which is involved in both productive and destructive processing of different antigen substrates. Overall, while there is undoubtedly redundancy in class II MHC antigen processing, the contributions of individual enzymes can be clearly dissected.