RNA Polymerase II Inhibitors Dissociate Antigenic Peptide Generation from Normal Viral Protein Synthesis: A Role for Nuclear Translation in Defective Ribosomal Product Synthesis?

Dolan, Brian P.; Knowlton, Jonathan J.; David, Alexandre; Bennink, Jack R.; Yewdell, Jonathan W.

doi:10.4049/jimmunol.1002543

Cited by 39 publications

(39 citation statements)

References 34 publications

(39 reference statements)

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“…Previous reports have suggested that nuclear translation indeed can occur (27,(30)(31)(32), but the physiological context has remained obscure. Our data presented here indicate that a major portion of the substrates for the MHC class I pathway are synthesized in the early steps of mRNA maturation by a noncanonical translation mechanism within the nucleus and before introns are spliced out.…”

Section: Discussionmentioning

confidence: 99%

Translation of pre-spliced RNAs in the nuclear compartment generates peptides for the MHC class I pathway

Apcher

Millot

Daskalogianni

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The scanning of maturing mRNAs by ribosomes plays a key role in the mRNA quality control process. When ribosomes first engage with the newly synthesized mRNA, and if peptides are produced, is unclear, however. Here we show that ribosomal scanning of prespliced mRNAs occurs in the nuclear compartment, and that this event produces peptide substrates for the MHC class I pathway. Inserting antigenic peptide sequences in introns that are spliced out before the mRNAs exit the nuclear compartment results in an equal amount of antigenic peptide products as when the peptides are encoded from the main open reading frame (ORF). Taken together with the detection of intron-encoded nascent peptides and RPS6/RPL7-carrying complexes in the perinucleolar compartment, these results show that peptides are produced by a translation event occurring before mRNA splicing. This suggests that ribosomes occupy and scan mRNAs early in the mRNA maturation process, and suggests a physiological role for nuclear mRNA translation, and also helps explain how the immune system tolerates peptides derived from tissue-specific mRNA splice variants.MHC class I restricted antigen presentation | mRNA maturation | nuclear translation R NAs carrying premature termination codons or are recognized as defective in other aspects are prevented from further translation and disposed of by the nonsense-mediated decay (NMD) pathway (1). The detection of premature stop codons is mediated by the scanning ribosome; however, when the ribosomes first engage with the newly synthesized mRNA, and if this event results in the production of peptides, is unclear. Two observations from the field of immunology and the presentation of peptides on MHC class I molecules have highlighted some aspects relevant to the role of the ribosomes in the mRNA maturation process. The first observation is related to the detection of antigenic peptides originating from intron sequences, and the second is related to the observation that the synthesis of antigenic peptide substrates and full-length proteins are two spatiotemporarily distinct events (2-5).The presentation of antigenic peptides on MHC class I molecules allows CD8 + T cells to detect and eliminate cells in which the repertoire of peptide substrates has been altered owing to the presence of viruses or to changes in the presentation of endogenous antigens (6, 7). However, despite the key role of antigen presentation on MHC class I molecules in immune surveillance, the source of peptides for the MHC class I pathway is not yet known. Accumulating evidence indicates that the processing of alternative peptide substrates plays a major role, and that degradation products derived from full-length proteins have limited access to the MHC class I pathway (8-10). We recently demonstrated that pioneer translation products (PTPs) that form antigenic peptide substrates for the MHC class I pathway are produced by a translation event that is distinct from the canonical event giving rise to full-length proteins and does not require the cap-binding ...

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Section: Discussionmentioning

confidence: 99%

Translation of pre-spliced RNAs in the nuclear compartment generates peptides for the MHC class I pathway

Apcher

Millot

Daskalogianni

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…It was later reported that the generation of antigenic peptides from DRiPs was from 25-fold to 65-fold more efficient than from "retirees" (11). These observations led to the speculation that there was a specialized biosynthetic pathway and/or compartmentalization that might supply DRiPs directly to the antigen presentation pathway (12,13).…”

Section: Immunology | Virology | Infectionmentioning

confidence: 97%

Using intein catalysis to probe the origin of major histocompatibility complex class I-presented peptides

Farfán-Arribas

Stern

Rock

2012

Proc. Natl. Acad. Sci. U.S.A.

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All vertebrate nucleated cells generate peptides from their expressed gene products and then display them at the cell surface bound to MHC class I molecules. This allows CD8 + T cells to detect and eliminate abnormal cells that are synthesizing foreign proteins, e.g., from viruses or mutations. To permit the immune system to more uniformly monitor a cell's proteins, regardless of their half-life or location, it has been thought that the products of rapid degradation of the mistakes of protein synthesis (defective ribosomal products, DRiPs) preferentially contribute to the class I-presented peptides. However, using intein catalysis to generate peptide sequences exclusively by posttranslational splicing of mature proteins, we show here that presented peptides can be generated from fully folded and functional proteins. Remarkably, the presentation of peptides from two model mature proteins is just as efficient as from newly synthesized proteins subject to errors in translation or folding. These results indicate that for the constructs we have analyzed, DRiPs are not a more efficient source of class I peptides for antigen presentation than the turnover of mature functional proteins. Accordingly, our data suggest that one of the major ways the immune system evaluates the health of cells is by monitoring the breakdown products of the proteome.

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“…Although their findings are indirect, Dolan et al [82] found that blocking mRNA synthesis with RNA polymerase II inhibitors reduces overall class I expression by ϳ35%, consistent with substantial peptide generation from nascent mRNAs. On the other hand, Pastor et al [83] found that shRNA-mediated interference with factors required for NMD (Smg1 or Upf2), enhanced in vivo elimination of tumor cells by OT-I cells (T cells specific for K b -SIINFEKL complexes) if SIINFEKL were expressed upstream from a premature termination codon.…”

Section: Rna Surveillancementioning

confidence: 99%

“…Almost 10 years later, Dolan et al [82] found that blocking nuclear export of influenza A virus neuraminidase mRNA disproportionally spared peptide versus native protein expression and proposed that nuclear translation participates in immunosurveillance. David et al [150] developed the RPM to identify translating ribosomes and found a robust signal in the nucleoplasm and nucleus.…”

Section: Nuclear Translation: Who Ordered That?mentioning

confidence: 99%

Translating DRiPs: MHC class I immunosurveillance of pathogens and tumors

Antón

Yewdell

2014

Journal of Leukocyte Biology

108

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MHC class I molecules display oligopeptides on the cell surface to enable T cell immunosurveillance of intracellular pathogens and tumors. Speed is of the essence in detecting viruses, which can complete a full replication cycle in just hours, whereas tumor detection is typically a finding-the-needle-in-the-haystack exercise. We review current evidence supporting a nonrandom, compartmentalized selection of peptidogenic substrates that focuses on rapidly degraded translation products as a main source of peptide precursors to optimize immunosurveillance of pathogens and tumors.

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RNA Polymerase II Inhibitors Dissociate Antigenic Peptide Generation from Normal Viral Protein Synthesis: A Role for Nuclear Translation in Defective Ribosomal Product Synthesis?

Cited by 39 publications

References 34 publications

Translation of pre-spliced RNAs in the nuclear compartment generates peptides for the MHC class I pathway

Translation of pre-spliced RNAs in the nuclear compartment generates peptides for the MHC class I pathway

Using intein catalysis to probe the origin of major histocompatibility complex class I-presented peptides

Translating DRiPs: MHC class I immunosurveillance of pathogens and tumors

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