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The Emerging Role of uORF-Encoded uPeptides and HLA uLigands in Cellular and Tumor Biology

SIMPLE SUMMARY: The biological relevance of peptides that originate from non-canonical translational initiation sites have been increasingly recognized over the years. Peptides encoded by open reading frames upstream of canonical protein coding sequences are frequently translated and act as translat...

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Autores principales: Jürgens, Lara, Wethmar, Klaus
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9776223/
https://www.ncbi.nlm.nih.gov/pubmed/36551517
http://dx.doi.org/10.3390/cancers14246031
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author Jürgens, Lara
Wethmar, Klaus
author_facet Jürgens, Lara
Wethmar, Klaus
author_sort Jürgens, Lara
collection PubMed
description SIMPLE SUMMARY: The biological relevance of peptides that originate from non-canonical translational initiation sites have been increasingly recognized over the years. Peptides encoded by open reading frames upstream of canonical protein coding sequences are frequently translated and act as translational regulators, contribute to the immunopeptidome as cellular antigens, and are implicated in various cellular functions through peptide–protein interactions or as part of protein complexes. In this review, we first give an overview of the most relevant technical advances in non-canonical peptide detection. In the second part of the review, we focus on the functional implications of uPeptides and delineate how this largely unexplored compartment of the human peptidome affects tumor biology and may offer new opportunities for targeted and immunological cancer therapy. ABSTRACT: Recent technological advances have facilitated the detection of numerous non-canonical human peptides derived from regulatory regions of mRNAs, long non-coding RNAs, and other cryptic transcripts. In this review, we first give an overview of the classification of these novel peptides and summarize recent improvements in their annotation and detection by ribosome profiling, mass spectrometry, and individual experimental analysis. A large fraction of the novel peptides originates from translation at upstream open reading frames (uORFs) that are located within the transcript leader sequence of regular mRNA. In humans, uORF-encoded peptides (uPeptides) have been detected in both healthy and malignantly transformed cells and emerge as important regulators in cellular and immunological pathways. In the second part of the review, we focus on various functional implications of uPeptides. As uPeptides frequently act at the transition of translational regulation and individual peptide function, we describe the mechanistic modes of translational regulation through ribosome stalling, the involvement in cellular programs through protein interaction and complex formation, and their role within the human leukocyte antigen (HLA)-associated immunopeptidome as HLA uLigands. We delineate how malignant transformation may lead to the formation of novel uORFs, uPeptides, or HLA uLigands and explain their potential implication in tumor biology. Ultimately, we speculate on a potential use of uPeptides as peptide drugs and discuss how uPeptides and HLA uLigands may facilitate translational inhibition of oncogenic protein messages and immunotherapeutic approaches in cancer therapy.
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spelling pubmed-97762232022-12-23 The Emerging Role of uORF-Encoded uPeptides and HLA uLigands in Cellular and Tumor Biology Jürgens, Lara Wethmar, Klaus Cancers (Basel) Review SIMPLE SUMMARY: The biological relevance of peptides that originate from non-canonical translational initiation sites have been increasingly recognized over the years. Peptides encoded by open reading frames upstream of canonical protein coding sequences are frequently translated and act as translational regulators, contribute to the immunopeptidome as cellular antigens, and are implicated in various cellular functions through peptide–protein interactions or as part of protein complexes. In this review, we first give an overview of the most relevant technical advances in non-canonical peptide detection. In the second part of the review, we focus on the functional implications of uPeptides and delineate how this largely unexplored compartment of the human peptidome affects tumor biology and may offer new opportunities for targeted and immunological cancer therapy. ABSTRACT: Recent technological advances have facilitated the detection of numerous non-canonical human peptides derived from regulatory regions of mRNAs, long non-coding RNAs, and other cryptic transcripts. In this review, we first give an overview of the classification of these novel peptides and summarize recent improvements in their annotation and detection by ribosome profiling, mass spectrometry, and individual experimental analysis. A large fraction of the novel peptides originates from translation at upstream open reading frames (uORFs) that are located within the transcript leader sequence of regular mRNA. In humans, uORF-encoded peptides (uPeptides) have been detected in both healthy and malignantly transformed cells and emerge as important regulators in cellular and immunological pathways. In the second part of the review, we focus on various functional implications of uPeptides. As uPeptides frequently act at the transition of translational regulation and individual peptide function, we describe the mechanistic modes of translational regulation through ribosome stalling, the involvement in cellular programs through protein interaction and complex formation, and their role within the human leukocyte antigen (HLA)-associated immunopeptidome as HLA uLigands. We delineate how malignant transformation may lead to the formation of novel uORFs, uPeptides, or HLA uLigands and explain their potential implication in tumor biology. Ultimately, we speculate on a potential use of uPeptides as peptide drugs and discuss how uPeptides and HLA uLigands may facilitate translational inhibition of oncogenic protein messages and immunotherapeutic approaches in cancer therapy. MDPI 2022-12-07 /pmc/articles/PMC9776223/ /pubmed/36551517 http://dx.doi.org/10.3390/cancers14246031 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Jürgens, Lara
Wethmar, Klaus
The Emerging Role of uORF-Encoded uPeptides and HLA uLigands in Cellular and Tumor Biology
title The Emerging Role of uORF-Encoded uPeptides and HLA uLigands in Cellular and Tumor Biology
title_full The Emerging Role of uORF-Encoded uPeptides and HLA uLigands in Cellular and Tumor Biology
title_fullStr The Emerging Role of uORF-Encoded uPeptides and HLA uLigands in Cellular and Tumor Biology
title_full_unstemmed The Emerging Role of uORF-Encoded uPeptides and HLA uLigands in Cellular and Tumor Biology
title_short The Emerging Role of uORF-Encoded uPeptides and HLA uLigands in Cellular and Tumor Biology
title_sort emerging role of uorf-encoded upeptides and hla uligands in cellular and tumor biology
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9776223/
https://www.ncbi.nlm.nih.gov/pubmed/36551517
http://dx.doi.org/10.3390/cancers14246031
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