Translating DRiPs: MHC class I immunosurveillance of pathogens and tumors

Antón, Luis C.; Yewdell, Jonathan W.

doi:10.1189/jlb.1113599

Cited by 110 publications

(83 citation statements)

References 180 publications

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“…During host-protein synthesis, a fraction of proteins synthesized will have the characteristics of a DRiP, a protein which cannot achieve the function for which it was intended and would be rapidly degraded. The fraction of nascent protein that qualifies as a DRiP has been estimated to be anywhere from 1 to 30% (41), but at this time we do not have an estimate for DRiP generation in our system. We do suspect that the DRiP fraction is small, as Western blot analysis of cells treated with Shield-1 and epoxomicin does not show an appreciable increase in SCRAP-SVG proteins compared to the level in Shield-1-treated cells without proteasome inhibition (Fig.…”

Section: Discussionmentioning

confidence: 98%

Enhanced Direct Major Histocompatibility Complex Class I Self-Antigen Presentation Induced by Chlamydia Infection

et al. 2016

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The direct major histocompatibility complex (MHC) class I antigen presentation pathway ensures intracellular peptides are displayed at the cellular surface for recognition of infected or transformed cells by CD8 ؉ cytotoxic T lymphocytes. Chlamydia spp. are obligate intracellular bacteria and, as such, should be targeted by CD8 ؉ T cells. It is likely that Chlamydia spp. have evolved mechanisms to avoid the CD8 ؉ killer T cell responses by interfering with MHC class I antigen presentation. Using a model system of self-peptide presentation which allows for posttranslational control of the model protein's stability, we tested the ability of various Chlamydia species to alter direct MHC class I antigen presentation. Infection of the JY lymphoblastoid cell line limited the accumulation of a model host protein and increased presentation of the model-protein-derived peptides. Enhanced selfpeptide presentation was detected only when presentation was restricted to defective ribosomal products, or DRiPs, and total MHC class I levels remained unaltered. Skewed antigen presentation was dependent on a bacterial synthesized component, as evidenced by reversal of the observed phenotype upon preventing bacterial transcription, translation, and the inhibition of bacterial lipooligosaccharide synthesis. These data suggest that Chlamydia spp. have evolved to alter the host antigen presentation machinery to favor presentation of defective and rapidly degraded forms of self-antigen, possibly as a mechanism to diminish the presentation of peptides derived from bacterial proteins.

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Section: Discussionmentioning

confidence: 98%

Enhanced Direct Major Histocompatibility Complex Class I Self-Antigen Presentation Induced by Chlamydia Infection

et al. 2016

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“…This may have resulted from a relatively greater expression of genes implicated in housekeeping functions, such as poly(A) RNA binding, mitotic cell cycle, and mRNA processing. Non-mutually exclusive hypotheses are that these genes have a preferential access to the MHC-processing machinery, for example, via "immunoribosomes," or that components of macromolecular complexes have a greater propensity to form DRiPs (17). Nonsource proteins were enriched in membrane components and related signaling processes, demonstrating that proteins traversing the secretory pathway are poorly represented in the MHCI immunopeptidome ( Figure 4B and Supplemental Table 4).…”

Section: Resultsmentioning

confidence: 99%

“…According to the dominant paradigm, MAPs preferentially originate from defective ribosomal products (DRiPs) which can be created by several mechanisms such as nonsense-mediated decay (NMD), mRNA destabilization, or noncanonical translation in the cytosol or the nucleus (16)(17)(18)(19)(20). Large-scale mass spectrometry (MS) offers the sole direct approach to analyzing the global molecular composition of the immunopeptidome.…”

Section: Introductionmentioning

confidence: 99%

MHC class I–associated peptides derive from selective regions of the human genome

Pearson¹,

Daouda²,

Granados³

et al. 2016

Journal of Clinical Investigation

179

218

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“…Antigens for MHC I loading have different origins (Farfan-Arribas et al, 2012). Besides the degradation of redundant or otherwise unwanted proteins, they also derive from defective ribosomal products (DRiPs) (Anton and Yewdell, 2014), which consist of prematurely terminated or mistranslated polypeptides. Although the C termini are already processed for ideal MHC I loading, the produced N termini are still disfavored.…”

Section: Generation Of a Short-lived Pool Of Peptidesmentioning

confidence: 99%

The transporter associated with antigen processing: a key player in adaptive immunity

Eggensperger

Tampé²

2015

Biological Chemistry

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Abstract:The adaptive immune system co-evolved with sophisticated pathways of antigen processing for efficient clearance of viral infections and malignant transformation. Antigenic peptides are primarily generated by proteasomal degradation and translocated into the lumen of the endoplasmic reticulum (ER) by the transporter associated with antigen processing (TAP). In the ER, peptides are loaded onto major histocompatibility complex I (MHC I) molecules orchestrated by a multisubunit peptide-loading complex (PLC). Peptide-MHC I complexes are targeted to the cell surface for antigen presentation to cytotoxic T cells, which eventually leads to the elimination of virally infected or malignantly transformed cells. Here, we review MHC I mediated antigen processing with a primary focus on the function and structural organization of the heterodimeric ATP-binding cassette (ABC) transporter TAP1/2. We discuss recent data on the molecular transport mechanism of the antigen translocation complex with respect to structural and biochemical information of other ABC exporters. We further summarize how TAP provides a scaffold for the assembly of the macromolecular PLC, thereby coupling peptide translocation with MHC I loading. TAP inhibition by distinct viral evasins highlights the important role of TAP in adaptive immunity.

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Translating DRiPs: MHC class I immunosurveillance of pathogens and tumors

Cited by 110 publications

References 180 publications

Enhanced Direct Major Histocompatibility Complex Class I Self-Antigen Presentation Induced by Chlamydia Infection

Enhanced Direct Major Histocompatibility Complex Class I Self-Antigen Presentation Induced by Chlamydia Infection

MHC class I–associated peptides derive from selective regions of the human genome

The transporter associated with antigen processing: a key player in adaptive immunity

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