Asparagine endopeptidase can initiate the removal of the MHC class II invariant chain chaperone

The invariant chain (li) chaperone for MHC class II molecules is crucial for their effective function. Equally important is its removal. Cathepsins S or L are known to be required for the final stages of li removal in different APCs, but the enzymes which initiate li processing have not been identified. Here we show that this step can be performed in B lymphocytes by asparagine endopeptidase (AEP), which targets different asparagine residues in the lumenal domain of human and mouse invariant chain. Inhibition of AEP activity slows invariant chain processing and hinders the expression of an antigenic peptide engineered to replace the groove binding region of li (CLIP). However, the initiation of li removal can also be performed by other proteases, reflecting the importance of this step.