Glycosylation signals that separate the trimerization from the MHC class II-binding domain control intracellular degradation of invariant chain

Invariant chain (Ii) serves as a chaperone for folding and intracellular tr ansport of major histocompatibility complex class II (MHCII) molecules. Ear ly in biosynthesis, Ii associates with MHCII molecules and directs their in tracellular transport to endocytic compartments where vesicular proteinases sequentially release Ii from the MHCII heterodimer. The detachment of Ii m akes the MHCII groove susceptible for binding of antigenic peptides. We inv estigated the role of N-linked glycosylation in the controlled intracellula r degradation of Ii. Motifs for asparagine-linked glycosylation were altere d, and mutated Ii (IiNmut) was transiently expressed in COS cells. The half -life of IiNmut was strongly reduced compared with wild-type Ii although th e sensitivity of the N glycan-free polypeptide to in vitro proteinase diges tion was not substantially increased. Inhibition of vesicular proteinases r evealed endosomal degradation of IiNmut. Intracellular proteolysis of IiNmu t is substantially impaired by serine proteinase inhibitors. Thus, a consid erable amount of IiNmut is degraded in nonacidic intracellular compartments . The data suggest that N-linked glycosylation of Ii hinders premature prot eolysis in nonacidic vesicles resulting in Ii degradation in acidic MHC cla ss II-processing compartments.