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

Val, Margarita Del; Iborra, Salvador; Ramos, Manuel; Lázaro, Silvia

doi:10.1007/s00018-011-0661-2

Cited by 26 publications

(5 citation statements)

References 71 publications

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“…The cytosol is a very degradative compartment, having multiple endoproteases and exopeptidases [1]. In contrast, both the vesicular compartments and the secretory pathway (source of TAP-independent ligands) are clearly less degradative [38]. Thus, the absence of high affinity ligands, generated by the TAP-dependent antigen processing, allows the interaction between the high amounts of empty HLA class I molecules and the long TAP-independent ligands with low affinity from TAP-deficient cells [8], [39].…”

Section: Discussionmentioning

confidence: 99%

Diversity of Natural Self-Derived Ligands Presented by Different HLA Class I Molecules in Transporter Antigen Processing-Deficient Cells

et al. 2013

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The transporter associated with antigen processing (TAP) translocates the cytosol-derived proteolytic peptides to the endoplasmic reticulum lumen where they complex with nascent human leukocyte antigen (HLA) class I molecules. Non-functional TAP complexes and viral or tumoral blocking of these transporters leads to reduced HLA class I surface expression and a drastic change in the available peptide repertoire. Using mass spectrometry to analyze complex human leukocyte antigen HLA-bound peptide pools isolated from large numbers of TAP-deficient cells, we identified 334 TAP-independent ligands naturally presented by four different HLA-A, -B, and -C class I molecules with very different TAP dependency from the same cell line. The repertoire of TAP-independent peptides examined favored increased peptide lengths and a lack of strict binding motifs for all four HLA class I molecules studied. The TAP-independent peptidome arose from 182 parental proteins, the majority of which yielded one HLA ligand. In contrast, TAP-independent antigen processing of very few cellular proteins generated multiple HLA ligands. Comparison between TAP-independent peptidome and proteome of several subcellular locations suggests that the secretory vesicle-like organelles could be a relevant source of parental proteins for TAP-independent HLA ligands. Finally, a predominant endoproteolytic peptidase specificity for Arg/Lys or Leu/Phe residues in the P1 position of the scissile bond was found for the TAP-independent ligands. These data draw a new and intricate picture of TAP-independent pathways.

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Section: Discussionmentioning

confidence: 99%

Diversity of Natural Self-Derived Ligands Presented by Different HLA Class I Molecules in Transporter Antigen Processing-Deficient Cells

et al. 2013

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“…During autophagy, large portions of cytoplasmic content, including proteins and organelles, are encapsulated in double membrane vesicles called autophagosomes ( 111 – 114 ). The autophagosomal membrane has been proposed to originate from the ER ( 115 , 116 ) and peptide-receptive MHC class I molecules might be present in autophagosomes, allowing for loading of peptides in these vesicular compartments ( 117 ). In addition, recirculating MHC class I molecules from the cell membrane end up in endosomes and can have contact with autophagosomes before returning to the endocytic network.…”

Section: Tap-independent Pathways: Alternative Routing To Mhc Class Imentioning

confidence: 99%

Alternative Antigen Processing for MHC Class I: Multiple Roads Lead to Rome

Oliveira

Hall

2015

Front. Immunol.

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The well described conventional antigen-processing pathway is accountable for most peptides that end up in MHC class I molecules at the cell surface. These peptides experienced liberation by the proteasome and transport by the peptide transporter TAP. However, there are multiple roads that lead to Rome, illustrated by the increasing number of alternative processing pathways that have been reported during last years. Interestingly, TAP-deficient individuals do not succumb to viral infections, suggesting that CD8 T cell immunity is sufficiently supported by alternative TAP-independent processing pathways. To date, a diversity of viral and endogenous TAP-independent peptides have been identified in the grooves of different MHC class I alleles. Some of these peptides are not displayed by normal TAP-positive cells and we therefore called them TEIPP, for “T-cell epitopes associated with impaired peptide processing.” TEIPPs are hidden self-antigens, are derived from normal housekeeping proteins, and are processed via unconventional processing pathways. Per definition, TEIPPs are presented via TAP-independent pathways, but recent data suggest that part of this repertoire still depend on proteasome and metalloprotease activity. An exception is the C-terminal peptide of the endoplasmic reticulum (ER)-membrane-spanning ceramide synthase Trh4 that is surprisingly liberated by the signal peptide peptidase (SPP), the proteolytic enzyme involved in cleaving leader sequences. The intramembrane cleaving SPP is thereby an important contributor of TAP-independent peptides. Its family members, like the Alzheimer’s related presenilins, might contribute as well, according to our preliminary data. Finally, alternative peptide routing is an emerging field and includes processes like the unfolded protein response, the ER-associated degradation, and autophagy-associated vesicular pathways. These data convince us that there is a world to be discovered in the field of unconventional antigen processing.

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“…Several alternative processing pathways come into consideration, including signal peptidases, Golgi peptidases as e.g. furin and ER-resident endoproteases which are responsible for cleavage of C-termini [29, 30]. However, how the ligands of the two latter TAP-independent pathways gain access to compartments where MHC-I molecule loading occurs remain elusive.…”

Section: Why Are Teipp Peptides Not Presented On Normal Cells?mentioning

confidence: 99%

A novel category of antigens enabling CTL immunity to tumor escape variants: Cinderella antigens

Seidel

Oliveira

Lampen

et al. 2011

Cancer Immunol Immunother

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Deficiencies in MHC class I antigen presentation are a common feature of tumors and allows escape from cytotoxic T lymphocyte (CTL)-mediated killing. It is crucial to take this capacity of tumors into account for the development of T-cell-based immunotherapy, as it may strongly impair their effectiveness. A variety of escape mechanisms has been described thus far, but progress in counteracting them is poor. Here we review a novel strategy to target malignancies with defects in the antigenic processing machinery (APM). The concept is based on a unique category of CD8+ T-cell epitopes that is associated with impaired peptide processing, which we named TEIPP. We characterized this alternative peptide repertoire emerging in MHC-I on tumors lacking classical antigen processing due to defects in the peptide transporter TAP (transporter associated with peptide processing). These TEIPPs exemplify interesting parallels with the folktale figure Cinderella: they are oppressed and neglected by a stepmother (like functional TAP prevents TEIPP presentation), until the suppression is released and Cinderella/TEIPP achieves unexpected recognition. TEIPP-specific CTLs and their cognate peptide-epitopes provide a new strategy to counteract immune evasion by APM defects and bear potential to targeting escape variants observed in a wide range of cancers.

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

Cited by 26 publications

References 71 publications

Diversity of Natural Self-Derived Ligands Presented by Different HLA Class I Molecules in Transporter Antigen Processing-Deficient Cells

Diversity of Natural Self-Derived Ligands Presented by Different HLA Class I Molecules in Transporter Antigen Processing-Deficient Cells

Alternative Antigen Processing for MHC Class I: Multiple Roads Lead to Rome

A novel category of antigens enabling CTL immunity to tumor escape variants: Cinderella antigens

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