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Review
. 2011 May;68(9):1543-52.
doi: 10.1007/s00018-011-0661-2. Epub 2011 Mar 9.

Generation of MHC class I ligands in the secretory and vesicular pathways

Margarita Del Val  1 , Salvador Iborra, Manuel Ramos, Silvia Lázaro
Affiliations
Review

Generation of MHC class I ligands in the secretory and vesicular pathways

Margarita Del Val et al. Cell Mol Life Sci. 2011 May.

Abstract

CD8(+) T lymphocytes screen the surface of all cells in the body to detect pathogen infection or oncogenic transformation. They recognize peptides derived from cellular proteins displayed at the plasma membrane by major histocompatibility complex (MHC) class I molecules. Peptides are mostly by-products of cytosolic proteolytic enzymes. Peptidic ligands of MHC class I molecules are also generated in the secretory and vesicular pathways. Features of protein substrates, of proteases and of available MHC class I molecules for loading peptides in these compartments shape a singular collection of ligands that also contain different, longer, and lower affinity peptides than ligands produced in the cytosol. Especially in individuals who lack the transporters associated with antigen processing, TAP, and in infected and tumor cells where TAP is blocked, which thus have no supply of peptides derived from the cytosol, MHC class I ligands generated in the secretory and vesicular pathways contribute to shaping the CD8(+) T lymphocyte response.

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Figures

Fig. 1
Fig. 1
Generation of MHC class I ligands in the secretory and vesicular compartments. Peptides generated by proteasomes and other cytosolic proteases are transported to the ER via TAP. In cells deficient in TAP, membrane (1a) and secretory proteins (1b) are translocated into the ER because of their signal or transmembrane sequences. Several putative mechanisms might allow cytosolic proteins and peptides to gain access to secretory and vesicular compartments: diffusion through membranes (1c); transport through an altered ER translocon or an unidentified ER transporter (1d); transport through an unidentified endolysosomal transporter (1e); and autophagy (1f). Endoproteolytic antigen processing in the ER relies on signal peptidase and other undefined endoproteases (2a). Two proprotein convertases have been shown to process antigens in the absence of TAP: furin, located in the trans-Golgi network (2b), and PC7, located in trans-Golgi network and endocytic vesicles (2b, 2c). Cathepsins have been involved in the generation of MHC class I ligands in endolysosomal compartments (2c). Most of the products generated by these endoproteases require trimming by aminopeptidases like ERAP and by a putative carboxypeptidase in the secretory pathway (3). The canonical binding site for MHC class I ligands is the ER (4a). Alternatively peptides might be exchanged at quality control sites in the Golgi (4b) or at endosomes containing MHC class I molecules that undergo constitutive recycling (4c). Finally, MHC class I ligands generated in the secretory and vesicular routes are presented to CD8+ T lymphocytes (5). White arrows indicate forward and retrograde transport of antigens across membranes, and grey arrows indicate putative transport. Potential proteases are in lower case
Fig. 2
Fig. 2
Features of MHC class I ligands generated in the secretory and vesicular pathways and identified in large-scale proteomic analyses. a For the four different MHC class I allotypes indicated, the fraction of ligands derived from luminal and transmembrane regions of parental proteins is depicted in dark grey, while light grey represents the fraction of ligands derived from non-vesicular proteins (cytosolic, nuclear, mitochondrial). b Global analysis of the luminal and non-vesicular ligands shown in a. Among luminal ligands, 90% are derived from secretory and type I membrane proteins, while 10% are derived from type II, III or IV membrane proteins. c Depending on the MHC class I allotype, signal sequence-derived ligands account for 20 to 90% of the secretory and type I ligands (20% for Kd, 25% for Qa-1b, 80% for HLA-B51 and 90% for HLA-A2). Within signal peptides, signal peptidase generates the exact carboxy terminus of the ligands in almost half of the cases (all 15 of them presented by HLA-A2), whereas carboxy terminal trimming is required for the other half (presented by all four allotypes). In all cases amino terminal trimming is necessary. Ligands derived from luminal regions of the proteins other than the signal sequence also require amino terminal trimming except in two cases in which signal peptidase generates the exact amino terminus of the ligand. Dotted lines represent signal peptidase cleavage, and scissors indicate exopeptidase trimming. d The localization of ligands derived from type II, III or IV transmembrane proteins is shown. They frequently constitute the exact carboxy terminus of the parental protein. Original data from [–44]
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