Initial proteolyis of Ii by aspartic proteases to lip22

Stable Identifier
Reaction [transition]
Homo sapiens
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Within acidic endocytic compartments Ii is proteolytically cleaved, ultimately freeing the class II peptide-binding groove for loading of antigenic peptides. Ii is degraded in a stepwise manner by a combination of aspartyl and cysteine proteases, following a well defined path with intermediates lip22, lip10 and finally CLIP. The initial Ii cleavage has been ascribed to leupeptin-insensitive cysteine or aspartic proteases, which include aspartyl protease and asparagine endopeptidase (AEP) (Maric et al. 1994, Manoury et al. 2003, Costantino et al. 2008). These proteases generate 22 kDa fragments of Ii (lip22). The trimerization domain of human Ii (residues 134-208) has three possible AEP cleavage sites, Asn148, 165 and 171. Asn171, located at the C-terminal end of helix B, is the demonstrated cleavage site for AEP (Manoury et al. 2003, Jasanoff et al. 1998). This cleavage eliminates the C-terminal trimerization domain of Ii, which causes disassociation of the (MHC II:Ii)3 nonamer and exposes new cleavage sites in the MHC II:lip22 trimers (Villadangos et al. 1999, Guillaume et al. 2008). The residue numbering of Ii given above is based on Uniprot isoform 1.

Literature References
PubMed ID Title Journal Year
18292509 Lysosomal cysteine and aspartic proteases are heterogeneously expressed and act redundantly to initiate human invariant chain degradation

Costantino, CM, Ploegh, HL, Hafler, DA, Kent, SC, Hang, HC

J Immunol 2008
8134367 Endosomal aspartic proteinases are required for invariant-chain processing

Taylor, MD, Blum, JS, Mari?, MA

Proc Natl Acad Sci U S A 1994
Catalyst Activity

cysteine-type endopeptidase activity of LGMN [lysosomal lumen]

Orthologous Events
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