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The Role of Insulin Regulated Aminopeptidase in Endocytic The Role of Insulin Regulated Aminopeptidase in Endocytic Trafficking and Receptor Signaling in Immune Cells Delphyne Descamps, Irini Evnouchidou, Vivien Caillens, Carole Drajac, Sabine Riffault, Peter van Endert, Loredana Saveanu To cite this version: Delphyne Descamps, Irini Evnouchidou, Vivien Caillens, Carole Drajac, Sabine Riffault, et al.. The Role of Insulin Regulated Aminopeptidase in Endocytic Trafficking and Receptor Signaling in Immune Cells. Frontiers in Molecular Biosciences, Frontiers Media, 2020, 7, 10.3389/fmolb.2020.583556. hal- 02972353 HAL Id: hal-02972353 https://hal.archives-ouvertes.fr/hal-02972353 Submitted on 20 Oct 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution| 4.0 International License fmolb-07-583556 October 14, 2020 Time: 17:1 # 1 REVIEW published: 20 October 2020 doi: 10.3389/fmolb.2020.583556 The Role of Insulin Regulated Aminopeptidase in Endocytic Trafficking and Receptor Signaling in Immune Cells Delphyne Descamps1*, Irini Evnouchidou2,3, Vivien Caillens2, Carole Drajac1, Sabine Riffault1, Peter van Endert2,4,5 and Loredana Saveanu2* 1 Université Paris-Saclay, INRAE, UVSQ, VIM, Jou-en-Josas, France, 2 Université de Paris, Centre de recherche sur l’inflammation, INSERM U1149, CNRS ERL8252, Paris, France, 3 Inovarion, Paris, France, 4 Université de Paris, INSERM Unité 1151, CNRS UMR 8253, Paris, France, 5 Service d’immunologie biologique, AP-HP, Hôpital Necker, Paris, France Edited by: Insulin regulated aminopeptidase (IRAP) is a type II transmembrane protein with Efstratios Stratikos, broad tissue distribution initially identified as a major component of Glut4 storage National Centre of Scientific Research vesicles (GSV) in adipocytes. Despite its almost ubiquitous expression, IRAP had been Demokritos, Greece extensively studied mainly in insulin responsive cells, such as adipocytes and muscle Reviewed by: Angeliki Chroni, cells. In these cells, the enzyme displays a complex intracellular trafficking pattern National Centre of Scientific Research regulated by insulin. Early studies using fusion proteins joining the IRAP cytosolic domain Demokritos, Greece Susanna R. Keller, to various reporter proteins, such as GFP or the transferrin receptor (TfR), showed that University of Virginia, United States the complex and regulated trafficking of the protein depends on its cytosolic domain. *Correspondence: This domain contains several motifs involved in IRAP trafficking, as demonstrated Delphyne Descamps by mutagenesis studies. Also, proteomic studies and yeast two-hybrid experiments [email protected] Loredana Saveanu showed that the IRAP cytosolic domain engages in multiple protein interactions with [email protected] cytoskeleton components and vesicular trafficking adaptors. These findings led to Specialty section: the hypothesis that IRAP is not only a cargo of GSV but might be a part of the This article was submitted to sorting machinery that controls GSV dynamics. Recent work in adipocytes, immune Cellular Biochemistry, cells, and neurons confirmed this hypothesis and demonstrated that IRAP has a dual a section of the journal Frontiers in Molecular Biosciences function. Its carboxy-terminal domain located inside endosomes is responsible for the Received: 15 July 2020 aminopeptidase activity of the enzyme, while its amino-terminal domain located in the Accepted: 25 September 2020 cytosol functions as an endosomal trafficking adaptor. In this review, we recapitulate the Published: 20 October 2020 published protein interactions of IRAP and summarize the increasing body of evidence Citation: Descamps D, Evnouchidou I, indicating that IRAP plays a role in intracellular trafficking of several proteins. We describe Caillens V, Drajac C, Riffault S, the impact of IRAP deletion or depletion on endocytic trafficking and the consequences van Endert P and Saveanu L (2020) on immune cell functions. These include the ability of dendritic cells to cross-present The Role of Insulin Regulated Aminopeptidase in Endocytic antigens and prime adaptive immune responses, as well as the control of innate and Trafficking and Receptor Signaling adaptive immune receptor signaling and modulation of inflammatory responses. in Immune Cells. Front. Mol. Biosci. 7:583556. Keywords: IRAP, endosome trafficking, immune cell responses, receptor signaling, formin, vacuolar protein doi: 10.3389/fmolb.2020.583556 sorting, TLR9, TCR Frontiers in Molecular Biosciences| www.frontiersin.org 1 October 2020| Volume 7| Article 583556 fmolb-07-583556 October 14, 2020 Time: 17:1 # 2 Descamps et al. IRAP and Intracellular Trafficking IRAP IDENTIFICATION AND TISSUE aminopeptidases ERAP1 (synonyms A-LAP, PILSAP) and EXPRESSION ERAP2 (synonym L-RAP). Based on phylogenetic analyses, IRAP, ERAP1, and ERAP2 were classified in a distinct group The IRAP (insulin regulated or responsive aminopeptidase) of M1 aminopeptidases named “oxytocinase subfamily of M1 protein is encoded by the human gene LNPEP. Although aminopeptidases” (Tsujimoto and Hattori, 2005). Even though IRAP is the most commonly used name for this protein, all three enzymes are able to trim the N-terminus of antigenic other names related to the various substrates cleaved by the peptides, they do so in different patterns consistent with the need enzyme are also used, such as oxytocinase, OTASE, leucyl and to produce epitopes in different antigen presentation pathways: cystinyl aminopeptidase, placental leucine aminopeptidase (P- ERAP1 and ERAP2 mainly contributing to direct MHC-I LAP), cystinyl aminopeptidase (CAP), and vasopressinase. presentation (Saveanu et al., 2005; Weimershaus et al., 2013) and While placental leucine aminopeptidase activities were IRAP to cross-presentation (Saveanu et al., 2009; Segura et al., described more than 50 years ago (Beckman et al., 1966, 2009; Weimershaus et al., 2012). The elucidation of the crystal 1969), DNA sequences coding for IRAP were first identified structures of IRAP, ERAP1, and ERAP2 in combination with in 1995 from a rat adipose tissue cDNA library (Keller biochemical studies revealed differences in substrate specificity et al., 1995) and 1 year later from a human placental cDNA and mechanism of action (Nguyen et al., 2011; Evnouchidou library (Rogi et al., 1996). Soon after its identification, IRAP et al., 2012, 2014; Mpakali et al., 2015a,b, 2017a) that could also intracellular distribution was analyzed in adipocytes, where explain different antigen processing by different cell types (Segura in basal conditions the enzyme colocalizes with the regulated et al., 2009; Weimershaus et al., 2012; Dinter et al., 2014; Mpakali glucose transporter, Glut4, in intracellular vesicles called Glut4 et al., 2017b). IRAP was the last member of this subfamily storage vesicles (GSV) (Ross et al., 1996). Upon adipocyte to have its crystal structure resolved (Mpakali et al., 2015b). stimulation by insulin, IRAP, like Glut4, rapidly translocates to This delay was mainly due to the presence of a cytoplasmic the cell surface from where it is rapidly endocytosed with a and transmembrane domain, which make the expression and half-life of about 3 to 5 min, probably via a clathrin-mediated purification of the full-length protein very difficult, as well as endocytic pathway (Summers et al., 1999). Even though the vast its high degree of glycosylation, which is a major hurdle for the majority of studies on IRAP had been performed in adipocytes, acquisition of high-quality crystals suitable for crystallography. already Keller et al.(1995) detected the protein by immunoblot Therefore, much information on the enzyme structure came in several tissues, such as heart, brain, spleen, lung, muscles, earlier from biochemical studies. and kidney. The wide tissue distribution of IRAP has been IRAP is a type-II membrane-spanning protein that has a confirmed by Mizutani’s group which detected IRAP at mRNA cytoplasmic domain composed of 109 amino acids, followed by and protein level in placental syncytiotrophoblasts, endothelial a 23-amino acid transmembrane domain and an extracellular or cells, gastrointestinal tract, several epithelial cell types from intraluminal (depending on its localization inside the cell) 893- the liver, pancreas, lung, and kidney, as well as neuronal cells amino acid domain. The extracellular domain bears the Zn2C (Nagasaka et al., 1997). They concluded that the broad tissue binding and GAMEN motifs that are essential for the enzyme’s distribution of IRAP is suggestive for a much more complex and aminopeptidase activity (Keller et al., 1995). Unlike murine IRAP, varied function of the protein beyond the regulation of oxytocin the human protein bears a putative cleavage site for ADAM12 and vasopressin levels in the blood. (F154/A155) that after proteolysis allows the release of a soluble Further studies confirmed the almost ubiquitous IRAP form detectable in the serum during pregnancy (Iwase et al., expression and its involvement in a variety of physiological 2001; Ofner and Hooper, 2002; Ito et al., 2004). The targeting
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