Assembly transport and peptide loading of class II molecules

The assembly of class II molecules occurs in the endoplasmic reticulum. The first event in this process is trimerization of the invariant chain (Ii) with which intracellular class II associates. Immediately after formation, this trimer associates with a pair of a and 3 chains, and two more heterodimers subsequently associate, to form a nonameric complex (Figure 4).

The chaperones immunoglobulin-binding protein (BiP) and calnexin enhance this process. The non-amers then travel across the Golgi and trans-Golgi to endosomal compartments. The nonameric complexes are unable to bind peptides, and there is strong experimental evidence that Ii plays an important role in preventing this association. Two different sequence motifs present in the Ii cytoplasmic domain have been shown to contribute to endosomal transport of class II, but Ii-independent transport has also been shown to occur. Sequences within the cytoplasmic domains of class II molecules themselves have been implicated in the regulation of Ii-independent transport.

Following endosomal localization, Ii is degraded by aspartic and thiol proteases into a nested set of peptides spanning Ii residues 81-104. This peptides are termed CLIPs. CLIPs associate with the peptide-binding groove of a|3 heterodimers, blocking their association with antigenic peptides. Removal of the CLIP peptides, which must precede normal class II peptide loading, is enhanced by the products of the H2M locus (see Figure 1). Recent evidence shows that these molecules directly promote CLIP release, as well as the release of peptides which bind class

Endoplasmic reticulum Golgi Endocytic compartment

Figure 4 Class II assembly and transport to the cell membrane. Details of the process are described in the text.

Endoplasmic reticulum Golgi Endocytic compartment

Figure 4 Class II assembly and transport to the cell membrane. Details of the process are described in the text.

II relatively weakly. Antigenic peptides which bind tightly are not susceptible to this enhanced release. The specific nature of the endosomal compartment where class II associates with exogenously derived antigenic peptides is not completely defined. A large body of evidence indicates that peptide association and CLIP dissociation is favored by an acidic environment, such as that found in late endosomes and lysosomes. However, data from a large number of studies suggest that class II molecules are found to some extent at many levels in the endocytic system. Several studies have also suggested the existence of a specialized class Il-containing compartment, distinct from previously characterized endosomal/lysosomal compartments, called the MIIC. MIICs show a multilamellar structure and contain lysosomal enzymes; this compartment may have a specialized role in class II antigen presentation.

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