Abstract
Production of MHC-I ligands from antigenic proteins generally requires multiple proteolytic events. While the proteolytic steps required for antigen processing in the endogenous pathway are clearly established, persisting gaps of knowledge regarding putative cross-presentation compartments have made it difficult to map the precise proteolytic events required for generation of cross-presented antigens. It is only in the past decade that the importance of aminoterminal trimming as the final step in the endogenous presentation pathway has been recognized and that the corresponding enzymes have been described. This review focuses on the aminoterminal trimming of exogenous cross-presented peptides, with particular emphasis on the identification of insulin responsive aminopeptidase (IRAP) as the principal trimming aminopeptidase in endosomes and phagosomes.
Highlights
HISTORY Insulin responsive aminopeptidase (IRAP) was initially identified due to its abundance in adipocytes, in specialized endosomes called Glut4 storage vesicles (GSV)
The discovery of the glucose transporter Glut4 in 1989 (Birnbaum, 1989; James et al, 1989) was followed by sustained efforts to identify the biochemical composition of GSV, which revealed an abundant protein with a MW of around 160–165 kDa that was constantly associated with isolated GSV and called vp 165
We have found that IRAP was strongly recruited to early phagosomes, where it colocalized with internalized MHC class I and phagocytized antigen
Summary
The human IRAP gene codes for a type II transmembrane protein with three domains: a cytoplasmic N-terminal domain of 109-amino-acid, a transmembrane domain of 23-amino-acid, and an intraluminal (or extracellular) domain of 893 amino acids, which include 16 potential N-glycosylation sites (Keller et al, 1995). The long C-terminal, intra-endosomal domain contains a Zn-binding motif HEXXH(X)18E and the exopeptidase motif GAMEN, which are encoded by exons 6 and 7. These two motifs are found in ERAP1 and ERAP2 and are shared by all members of the M1 family of aminopeptidases (Tsujimoto and Hattori, 2005). The principal difference between the protein sequences of IRAP and the other members of M1 metallopeptidase family, including ERAP1 and 2, is the N-terminal cytoplasmic IRAP domain, which is required for the enzyme localization and its complex intracellular trafficking (see below)
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