Mutation of the invariant chain transmembrane region inhibits Ii degradation, prolongs association with MHC class II, and selectively disrupts antigen presentation

The invariant chain (Ii) is a key player in regulating the MHC Class II antigen presentation pathway. Here we used site-directed mutagenesis to identify functionally important regions of the invariant chain in regulating antigen presentation function in transfected cells. Mutation of Ii residues 42-53 caused a defect in the presentation of the ovalbumin 247-265/A^k epitope, but not in the inhibition of presentation of two hen egg lysozyme epitopes, HEL34-45/A^k and HEL74-88/A^b, from endogenously expressed antigens. The mutation did not prevent ER translocation, trimerization, or association with MHC Class II molecules and had no obvious effect on endosomal targeting of Ii. It did, however, increase the half-life of the invariant chain, suggesting that sequences in this region influence the degradation of the invariant chain and as a consequence its function in antigen presentation.