Antigen presentation by major histocompatibility complex class I (MHC-I) molecules is a pivotal step in immunity: it enables the activation of CD8+ T lymphocytes, which are essential for defense against viruses, tumors, and intracellular pathogens. Generating, from long proteins, peptides of a size suited to the MHC-I binding groove requires several successive proteolytic steps. While the cytosolic proteasome plays a major role in this process, the identification in the early 2000s of an aminopeptidase activity in the endoplasmic reticulum substantially enriched this model. This review takes stock of the three aminopeptidases of the oxytocinase subfamily of M1 zinc metallopeptidases and, above all, of their functions that extend beyond the mere maturation of antigenic peptides.
Three enzymes make up this subfamily in humans: endoplasmic reticulum aminopeptidases 1 and 2 (ERAP1 and ERAP2), soluble enzymes of the reticulum lumen, and the insulin-regulated aminopeptidase (IRAP, or oxytocinase), a type II transmembrane protein localized in endosomes. Their genes partially overlap over a 263-kilobase segment of chromosome 5q15 and likely arose from gene duplication events. The protein sequences are highly conserved, with identities of 43 to 49% among the three enzymes. This apparent redundancy is also reflected in interspecies diversity: rodents lack the ERAP2 gene, whereas other species, such as birds, display variable combinations of the three genes. The ability of these enzymes to generate MHC-I ligands has been extensively documented for ERAP1, less so for ERAP2, and only in the context of cross-presentation for IRAP.
Beyond this canonical function, the authors compile the data attributing to these aminopeptidases roles distinct from antigenic trimming. IRAP stands out notably for its amino-terminal cytosolic domain, which carries acidic trafficking motifs necessary and sufficient for its endosomal localization and its regulated shuttling between endosomes and the plasma membrane; this domain interacts with components and remodeling proteins of the cytoskeleton, contributing to the stability of the endosomes that harbor it. The review also addresses the involvement of these enzymes in the regulation of blood pressure and the renin-angiotensin system, the cleavage of substrates such as vasopressin, and the remodeling of membrane receptors.
After twenty years of research, the enzymatic function of these proteins is well characterized, and their genetic association with autoimmune diseases, cancers, and infections is firmly established. The mechanisms linking these enzymes to human pathologies nonetheless remain incompletely elucidated. By synthesizing recent work on IRAP and ERAP2, this review highlights the new questions raised by their functions independent of antigenic trimming.