DNA damage promotes HLA class I presentation by stimulating a pioneer round of translation-associated antigen production

Uchihara, Yuki; Permata, Tiara Bunga Mayang; Sato, Hiro; Kawabata‐Iwakawa, Reika; Katada, Sayako; Gu, Wenchao; Kakoti, Sangeeta; Yamauchi, Motohiro; Kato, Reona; Gondhowiardjo, Soehartati; Hosen, Naoki; Yasuhara, Takaaki; Shibata, Atsushi

doi:10.1016/j.molcel.2022.04.030

Cited by 15 publications

(8 citation statements)

References 70 publications

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“…Finally, fusing the antigenic peptide to the IκBα sequence and inducing IκBα degradation did not show to have any impact on the presentation of the fused antigen, despite a giant increase in degradation substrates [14]. Recent studies show that DNA damage induces presentation of peptides coming from the pioneer round of translation in the nucleus [19]. Altogether undermined degradation of mature proteins as a source of AP.…”

Section: Discussionmentioning

confidence: 99%

Major Histocompatibility Complex class I heavy chains localize in both cytoplasmic and nuclear compartment

Gómez-Herranz

Dziadosz

Mikac

et al. 2022

Preprint

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The Major Histocompatibility Complex class I (MHC-I) molecules present antigenic peptides (AP) to CD8+ T cells for self versus non-self recognition. Loading of AP on MHC-I takes place in the endoplasmic reticulum (ER), upon shuttling of cytoplasmic AP substrates to the ER. Understanding of this process has been influenced by the view that MHC-I antigens are produced from the proteasomal degradation of cellular proteins. Recent observations on the intronic and untranslated region-derived peptides as well as on the non-AUG translation products presented on the MHC-I open the possibility that antigenic peptides can derive from pre-spliced mRNAs translated in the nuclear compartment. In this brief report, we show that a fraction of human MHC-I molecules (human leukocyte antigens type A, HLA-A) is present in the nuclei of cells, in the proximity of histone H2B. With this finding, we hope to initiate a new direction of research on the nuclear role of MHC-I and ask whether the loading of antigens can take place in the nuclear compartment.

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Section: Discussionmentioning

confidence: 99%

Major Histocompatibility Complex class I heavy chains localize in both cytoplasmic and nuclear compartment

Gómez-Herranz

Dziadosz

Mikac

et al. 2022

Preprint

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“…For example, the CBC was recently reported to interact with the RNA component of the signal recognition particle, thereby supporting appropriate targeting of signal sequence-containing proteins to the ER (Park et al, 2021). CBC-dependent translation was also reported to support some forms of antigen presentation, for example on MHC-I (Weinstein-Marom et al, 2019) and on class I HLA (Uchihara et al, 2022).…”

Section: The Native Rna Pathwaymentioning

confidence: 99%

Translation of in vitro-transcribed RNA therapeutics

Haar

Mulroney²,

Hedayioglu³

et al. 2023

Front. Mol. Biosci.

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In vitro transcribed, modified messenger RNAs (IVTmRNAs) have been used to vaccinate billions of individuals against the SARS-CoV-2 virus, and are currently being developed for many additional therapeutic applications. IVTmRNAs must be translated into proteins with therapeutic activity by the same cellular machinery that also translates native endogenous transcripts. However, different genesis pathways and routes of entry into target cells as well as the presence of modified nucleotides mean that the way in which IVTmRNAs engage with the translational machinery, and the efficiency with which they are being translated, differs from native mRNAs. This review summarises our current knowledge of commonalities and differences in translation between IVTmRNAs and cellular mRNAs, which is key for the development of future design strategies that can generate IVTmRNAs with improved activity in therapeutic applications.

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“…From this perspective, ribosome sequencing (ribo‐seq) and polysome sequencing (poly‐seq) are also actively introduced into immunopeptidomics to reflect the status even closer to the actual translation step than RNA‐seq. Transcriptomics data can include disease‐specific translations by alternative splicing such as aberrant translation under tryptophan deficiency 26,27 or the pioneer round of translation after DNA damage 28 . Although it has often been overlooked, and thus should be noted, the mutation in the exon–intron junction region can also evoke aberrant splicing 29,30 that still translated within the canonical ORF.…”

Section: Transformative Technologies That Shed Light Upon the Dark Ma...mentioning

confidence: 99%

Emerging potential of immunopeptidomics by mass spectrometry in cancer immunotherapy

Minegishi,

Haga,

Ueda

2024

Cancer Science

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With significant advances in analytical technologies, research in the field of cancer immunotherapy, such as adoptive T cell therapy, cancer vaccine, and immune checkpoint blockade (ICB), is currently gaining tremendous momentum. Since the efficacy of cancer immunotherapy is recognized only by a minority of patients, more potent tumor‐specific antigens (TSAs, also known as neoantigens) and predictive markers for treatment response are of great interest. In cancer immunity, immunopeptides, presented by human leukocyte antigen (HLA) class I, play a role as initiating mediators of immunogenicity. The latest advancement in the interdisciplinary multiomics approach has rapidly enlightened us about the identity of the “dark matter” of cancer and the associated immunopeptides. In this field, mass spectrometry (MS) is a viable option to select because of the naturally processed and actually presented TSA candidates in order to grasp the whole picture of the immunopeptidome. In the past few years the search space has been enlarged by the multiomics approach, the sensitivity of mass spectrometers has been improved, and deep/machine‐learning‐supported peptide search algorithms have taken immunopeptidomics to the next level. In this review, along with the introduction of key technical advancements in immunopeptidomics, the potential and further directions of immunopeptidomics will be reviewed from the perspective of cancer immunotherapy.

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DNA damage promotes HLA class I presentation by stimulating a pioneer round of translation-associated antigen production

Cited by 15 publications

References 70 publications

Major Histocompatibility Complex class I heavy chains localize in both cytoplasmic and nuclear compartment

Major Histocompatibility Complex class I heavy chains localize in both cytoplasmic and nuclear compartment

Translation of in vitro-transcribed RNA therapeutics

Emerging potential of immunopeptidomics by mass spectrometry in cancer immunotherapy

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