Abstract
Insulin regulated aminopeptidase (IRAP) is a type II transmembrane protein with broad tissue distribution initially identified as a major component of Glut4 storage vesicles (GSV) in adipocytes. Despite its almost ubiquitous expression, IRAP had been extensively studied mainly in insulin responsive cells, such as adipocytes and muscle cells. In these cells, the enzyme displays a complex intracellular trafficking pattern regulated by insulin. Early studies using fusion proteins joining the IRAP cytosolic domain to various reporter proteins, such as GFP or the transferrin receptor (TfR), showed that the complex and regulated trafficking of the protein depends on its cytosolic domain. This domain contains several motifs involved in IRAP trafficking, as demonstrated by mutagenesis studies. Also, proteomic studies and yeast two-hybrid experiments showed that the IRAP cytosolic domain engages in multiple protein interactions with cytoskeleton components and vesicular trafficking adaptors. These findings led to the hypothesis that IRAP is not only a cargo of GSV but might be a part of the sorting machinery that controls GSV dynamics. Recent work in adipocytes, immune cells, and neurons confirmed this hypothesis and demonstrated that IRAP has a dual function. Its carboxy-terminal domain located inside endosomes is responsible for the aminopeptidase activity of the enzyme, while its amino-terminal domain located in the cytosol functions as an endosomal trafficking adaptor. In this review, we recapitulate the published protein interactions of IRAP and summarize the increasing body of evidence indicating that IRAP plays a role in intracellular trafficking of several proteins. We describe the impact of IRAP deletion or depletion on endocytic trafficking and the consequences on immune cell functions. These include the ability of dendritic cells to cross-present antigens and prime adaptive immune responses, as well as the control of innate and adaptive immune receptor signaling and modulation of inflammatory responses.
Highlights
Delphyne Descamps1*, Irini Evnouchidou2,3, Vivien Caillens2, Carole Drajac1, Sabine Riffault1, Peter van Endert2,4,5 and Loredana Saveanu2*
In dendritic cells (DCs), the interaction between FHOD4 and Insulin regulated aminopeptidase (IRAP) is required for anchoring the endosomes containing TLR9 and its ligands to the cell periphery and avoiding their fusion with lysosomes (Babdor et al, 2017)
In bone marrow-derived DCs (BMDCs), IRAP colocalizes with Rab14 in peripheral endosomes and that both proteins are required for the formation and stabilization of Glut4 storage vesicles (GSV)-like vesicles in these cells
Summary
The IRAP (insulin regulated or responsive aminopeptidase) protein is encoded by the human gene LNPEP. Since the hydroxyl group of Tyr549, which is crucial for the formation of the catalytic intermediate, was not in a position allowing it to form a hydrogen bond, the authors proposed that the obtained structure is a snapshot of an inactive state of the enzyme They suggested that this structure corresponds to an enzyme-product complex, where the C-terminal domain swings out from the active site in order to allow product release. The GAMEN loop adopted a completely different position compared to other M1 aminopeptidases, which explains the unique ability of IRAP to cleave cyclic peptides such as oxytocin and vasopressin Another structure (3.3 Å) obtained by the group of Stratikos (Mpakali et al, 2015b) superposed completely with the first one. This attachment of palmitate and other fatty acids to a cysteine could mediate membrane attachment of soluble proteins, regulate intracellular trafficking and affect protein–protein
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