The role of insulin-regulated aminopeptidase in MHC class I antigen presentation - PubMed (original) (raw)

The role of insulin-regulated aminopeptidase in MHC class I antigen presentation

Loredana Saveanu et al. Front Immunol. 2012.

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.

Keywords: ERAP; IRAP; MHC class I; aminopeptidase; cross-presentation; dendritic cells.

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Figures

Figure 1

Figure 1

IRAP storage vesicles are slow recycling endosomes. Newly synthetized IRAP accumulates in storage endosomes as early as 3 h after transfection (Watson et al., 2004) and acquires insulin responsiveness after 6–9 h. During the first 3 h after enzyme synthesis, IRAP sorting from the ER is brefeldin A sensitive. Once the enzyme reaches the storage endosomes its translocation to the plasma membrane becomes insensitive to brefeldin A treatment (Watson et al., 2008). Sorting of newly synthetized IRAP from the TGN to the storage endosomes in adipocytes requires the GGA1 clathrin adaptor (Liu et al., ; Hou et al., 2006) and the LL76,77 sequence in the cytosolic domain of IRAP (Watson et al., 2008).

Figure 2

Figure 2

Cell-specific regulation of IRAP storage vesicles. (A) In insulin-responsive tissues, such as adipocytes and muscles, IRAP trafficking is regulated by insulin. Upon insulin binding to its receptor, PI3K-PDK1-Akt protein kinases are activated in a cascade. The most important effector in these cells seems to be the RabGAP AS160, which is phosphorylated by Akt2. Phosphorylation of AS160 leads to its dissociation from the storage endosomes and activation of Rab8, Rab10, and Rab14 that drive the endosome translocation to the cell surface. The biological effect is the increase at cell surface of the principal vesicle cargo, the glucose transporter GLUT4. (B) In other cells, the stimuli that regulate IRAP endosome trafficking and the signaling pathways involved in this process are poorly characterized. In DCs, IRAP endosomes are recruited rapidly to the phagosomal membrane. The phagocytic receptors and the signaling molecules responsible for this phenomenon are not yet identified.

Figure 3

Figure 3

Cross-presentation pathways. According to the involvement of the proteasome in antigen processing cross-presentation is divided in two main pathways: proteasome-dependent cross-presentation (left panel) and vacuolar cross-presentation (right panel). The vacuolar cross-presentation does not require proteasome activity; the entire antigen processing and MHC class I loading with cross-presented peptides occur inside the vacuole. The proteasome-dependent cross-presentation involves the transport of the exogenous antigens (possibly by Sec61) into the DC cytosol of the DC and generation of N-terminal extended precursors of MHC-I ligands in the cytosol. The aminoterminal trimming of these peptide precursors can occur in two different compartments: (i) in a cytosol to ER pathway, epitope precursors will join the endogenous processing pathway after their transport by TAP into the ER (Kovacsovics-Bankowski and Rock, 1995). In this case peptide trimming is carried out by ERAPs; (ii) in a cytosol to endosome pathway, the precursors of class I ligands are retro-transported into specialized endosomes (Burgdorf et al., ; Saveanu et al., 2009) or into phagosomes (Guermonprez et al., 2003) and final trimming is performed by IRAP (Saveanu et al., 2009).

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