The insulin-regulated aminopeptidase, known by the acronym IRAP and encoded by the human gene LNPEP, is a type II transmembrane protein expressed in most tissues. It was first identified in the 1990s as a major component of the storage vesicles of the glucose transporter Glut4 in adipocytes. For a long time, its study focused on insulin-sensitive cells, such as adipocytes and muscle cells, where the enzyme exhibits complex, insulin-regulated intracellular trafficking: in the basal state, it colocalizes with Glut4 in storage vesicles, then rapidly translocates to the plasma membrane upon insulin stimulation of the cell. This review compiles the knowledge accumulated on the functions of the protein and shifts the focus toward its role in immune cells.
Initial work, based on fusion proteins combining the cytosolic domain of IRAP with various reporters such as GFP or the transferrin receptor, established that the complex trafficking of the protein depends on this cytosolic domain. Mutagenesis studies identified several motifs involved in its targeting, while proteomic analyses and yeast two-hybrid experiments revealed that this same domain engages in multiple interactions with cytoskeletal components and vesicular trafficking adaptors. These observations led to the hypothesis that IRAP is not merely a constituent transported by vesicles, but also takes part in the sorting machinery that controls their dynamics.
More recent work, conducted in adipocytes, immune cells, and neurons, has confirmed this hypothesis by attributing a dual function to IRAP. Its carboxy-terminal domain, located within endosomes, carries the aminopeptidase activity of the enzyme, whereas its amino-terminal domain, exposed in the cytosol, acts as an endosomal trafficking adaptor. The authors thus catalog the full set of protein interactions described for IRAP and synthesize a growing body of evidence indicating that the protein is involved in the intracellular transport of several partners.
Finally, the synthesis details the consequences of IRAP deletion or depletion on endocytic trafficking and on immune functions. It notably highlights the importance of the protein for the ability of dendritic cells to perform cross-presentation of antigens and to initiate adaptive immune responses, as well as for the control of signaling by innate and adaptive immune receptors — among which the Toll-like receptor TLR9 and the T-cell receptor — and for the modulation of inflammatory responses.