The Iip10 fragment is converted subsequently to CLIP (class II–associated invariant chain peptide), a ∼3-kD peptide that is ultimately exchanged for antigenic peptide in the final step of peptide loading 5, 6, 7, 8, 9. The smallest fragment that contains both the NH 2-terminal endosomal targeting sequence and a COOH-terminal extension through the MHC class II peptide–binding groove has been termed Iip10. Within endosomal/lysosomal compartments, the Ii lumenal domain undergoes stepwise proteolytic degradation to yield progressively smaller fragments.
The Ii NH 2-terminal cytoplasmic domain contains an endosomal targeting signal that promotes Ii/MHC class II trafficking through the endosomal compartments of APCs 1, 2, 3, 4. Ii also regulates intracellular trafficking of MHC class II dimers. The MHC class II–associated invariant chain (Ii) is a type II transmembrane protein that binds to the peptide binding groove of newly synthesized MHC class II α/β heterodimers, thus preventing their premature association with endogenous polypeptides. Different APCs can thus use distinct proteases to mediate MHC class II maturation and peptide loading. These experiments show that cathepsin F, in a subset of antigen presenting cells (APCs), can efficiently degrade Ii. Inhibition of cathepsin F activity and MHC class II peptide loading by macrophages exhibited similar specificity and activity profiles.
Recombinant cathepsin Z did not generate CLIP from Ii–MHC class II complexes, whereas cathepsin F was as efficient as cathepsin S in CLIP generation. Comparison of cysteine proteases expressed by macrophages with those found in splenocytes and dendritic cells revealed two enzymes expressed exclusively in macrophages, cathepsins Z and F. Both processes are blocked by a cysteine protease inhibitor, indicating the involvement of an additional Ii-processing enzyme(s).
However, macrophages from mice deficient in both cathepsins S and L can process Ii and load peptides onto MHC class II dimers normally. Cathepsins L and S have both been implicated in degradation of Ii to CLIP in thymus and peripheral lymphoid organs, respectively. Such loading occurs after endosomal degradation of the invariant chain to a ∼3-kD peptide termed CLIP (class II–associated invariant chain peptide). The major histocompatibility complex (MHC) class II–associated invariant chain (Ii) regulates intracellular trafficking and peptide loading of MHC class II molecules.
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