II CHAIN CONTROLS THE TRANSPORT OF MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-II MOLECULES TO AND FROM LYSOSOMES

Major histocompatibility complex class II molecules are synthesized as a nonameric complex consisting of three ap dimers associated with a t rimer of invariant (Ii) chains. After exiting the TGN, a targeting sig nal in the Ii chain cytoplasmic domain directs the complex to endosome s where Ii chain is proteolytically processed and removed, allowing cl ass II molecules to bind antigenic peptides before reaching the cell s urface. Ii chain dissociation and peptide binding are thought to occur in one or more postendosomal sites related either to endosomes (desig nated CIIV) or to lysosomes (designated MIIC). We now find that in add ition to initially targeting crp dimers to endosomes, Ii chain regulat es the subsequent transport of class II molecules. Under normal condit ions, murine A20 B cells transport all of their newly synthesized clas s II I-Ab crp dimers to the plasma membrane with little if any reachin g lysosomal compartments. Inhibition of Ii processing by the cysteine/ serine protease inhibitor leupeptin, however, blocked transport to the cell surface and caused a dramatic but selective accumulation of I-A( b) class II molecules in lysosomes. In leupeptin, I-A(b) dimers formed stable complexes with a 10-kD NH2-terminal Ii chain fragment (Ii-p10) , normally a transient intermediate in Ii chain processing, Upon remov al of leupeptin, Ii-p10 was degraded and released, I-A(b) dimers bound antigenic peptides, and the peptide-loaded dimers were transported sl owly from lysosomes to the plasma membrane, Our results suggest that a lterations in the rate or efficiency of Ii chain processing can alter the postendosomal sorting of class II molecules, resulting in the incr eased accumulation of alpha beta dimers in lysosome-like MIIC. Thus, s imple differences in Ii chain processing may account for the highly va riable amounts of class II found in lysosomal compartments of differen t cell types or at different developmental stages.