bims-micpro Biomed News
on Discovery and characterization of microproteins
Issue of 2024–09–29
seven papers selected by
Thomas Farid Martínez, University of California, Irvine
  1. Upstream open reading frames repress the translation from the iab-8 RNA.
  2. Transcriptional junk: Waste or a key regulator in diverse biological processes?
  3. Evolution of translational control and the emergence of genes and open reading frames in human and non-human primate hearts.
  4. High-quality peptide evidence for annotating non-canonical open reading frames as human proteins.
  5. Multi-Omic Approaches in Cancer-Related Micropeptide Identification.
  6. RPFdb v3.0: an enhanced repository for ribosome profiling data and related content.
  7. The microprotein HDSP promotes gastric cancer progression through activating the MECOM-SPINK1-EGFR signaling axis.
  1. PLoS Genet. 2024 Sep 23. 20(9): e1011214
    Upstream open reading frames repress the translation from the iab-8 RNA.
    Yohan Frei, Clément Immarigeon, Maxime Revel, François Karch, Robert K Maeda.
      Although originally classified as a non-coding RNA, the male-specific abdominal (MSA) RNA from the Drosophila melanogaster bithorax complex has recently been shown to code for a micropeptide that plays a vital role in determining how mated females use stored sperm after mating. Interestingly, the MSA transcript is a male-specific version of another transcript produced in both sexes within the posterior central nervous system from an alternative promoter, called the iab-8 lncRNA. However, while the MSA transcript produces a small peptide, it seems that the iab-8 transcript does not. Here, we show that the absence of iab-8 translation is due to a repressive mechanism requiring the two unique 5' exons of the iab-8 lncRNA. Through cell culture and transgenic analysis, we show that this mechanism relies on the presence of upstream open reading frames present in these two exons that prevent the production of proteins from downstream open reading frames.
    DOI:  https://doi.org/10.1371/journal.pgen.1011214
  2. Curr Opin Plant Biol. 2024 Sep 26. pii: S1369-5266(24)00130-4. [Epub ahead of print]82 102639
    Transcriptional junk: Waste or a key regulator in diverse biological processes?
    Anwesha Anyatama, Tapasya Datta, Shambhavi Dwivedi, Prabodh Kumar Trivedi.
      Plant genomes, through their evolutionary journey, have developed a complex composition that includes not only protein-coding sequences but also a significant amount of non-coding DNA, repetitive sequences, and transposable elements, traditionally labeled as "junk DNA". RNA molecules from these regions, labeled as "transcriptional junk," include non-coding RNAs, alternatively spliced transcripts, untranslated regions (UTRs), and short open reading frames (sORFs). However, recent research shows that this genetic material plays crucial roles in gene regulation, affecting plant growth, development, hormonal balance, and responses to stresses. Additionally, some of these regulatory regions encode small proteins, such as miRNA-encoded peptides (miPEPs) and microProteins (miPs), which interact with DNA or nuclear proteins, leading to chromatin remodeling and modulation of gene expression. This review aims to consolidate our understanding of the diverse roles that these so-called "transcriptional junk" regions play in regulating various physiological processes in plants.
    Keywords:  Alternate splicing; Gene regulation; Untranslated regions; miRNA-encoded peptides; microProteins
    DOI:  https://doi.org/10.1016/j.pbi.2024.102639
  3. Nat Cardiovasc Res. 2024 Sep 24.
    Evolution of translational control and the emergence of genes and open reading frames in human and non-human primate hearts.
    Jorge Ruiz-Orera, Duncan C Miller, Johannes Greiner, Carolin Genehr, Aliki Grammatikaki, Susanne Blachut, Jeanne Mbebi, Giannino Patone, Anna Myronova, Eleonora Adami, Nikita Dewani, Ning Liang, Oliver Hummel, Michael B Muecke, Thomas B Hildebrandt, Guido Fritsch, Lisa Schrade, Wolfram H Zimmermann, Ivanela Kondova, Sebastian Diecke, Sebastiaan van Heesch, Norbert Hübner.
      Evolutionary innovations can be driven by changes in the rates of RNA translation and the emergence of new genes and small open reading frames (sORFs). In this study, we characterized the transcriptional and translational landscape of the hearts of four primate and two rodent species through integrative ribosome and transcriptomic profiling, including adult left ventricle tissues and induced pluripotent stem cell-derived cardiomyocyte cell cultures. We show here that the translational efficiencies of subunits of the mitochondrial oxidative phosphorylation chain complexes IV and V evolved rapidly across mammalian evolution. Moreover, we discovered hundreds of species-specific and lineage-specific genomic innovations that emerged during primate evolution in the heart, including 551 genes, 504 sORFs and 76 evolutionarily conserved genes displaying human-specific cardiac-enriched expression. Overall, our work describes the evolutionary processes and mechanisms that have shaped cardiac transcription and translation in recent primate evolution and sheds light on how these can contribute to cardiac development and disease.
    DOI:  https://doi.org/10.1038/s44161-024-00544-7
  4. bioRxiv. 2024 Sep 09. pii: 2024.09.09.612016. [Epub ahead of print]
    High-quality peptide evidence for annotating non-canonical open reading frames as human proteins.
    Eric W Deutsch, Leron W Kok, Jonathan M Mudge, Jorge Ruiz-Orera, Ivo Fierro-Monti, Zhi Sun, Jennifer G Abelin, M Mar Alba, Julie L Aspden, Ariel A Bazzini, Elspeth A Bruford, Marie A Brunet, Lorenzo Calviello, Steven A Carr, Anne-Ruxandra Carvunis, Sonia Chothani, Jim Clauwaert, Kellie Dean, Pouya Faridi, Adam Frankish, Norbert Hubner, Nicholas T Ingolia, Michele Magrane, Maria Jesus Martin, Thomas F Martinez, Gerben Menschaert, Uwe Ohler, Sandra Orchard, Owen Rackham, Xavier Roucou, Sarah A Slavoff, Eivind Valen, Aaron Wacholder, Jonathan S Weissman, Wei Wu, Zhi Xie, Jyoti Choudhary, Michal Bassani-Sternberg, Juan Antonio Vizcaíno, Nicola Ternette, Robert L Moritz, John R Prensner, Sebastiaan van Heesch.
      A major scientific drive is to characterize the protein-coding genome as it provides the primary basis for the study of human health. But the fundamental question remains: what has been missed in prior genomic analyses? Over the past decade, the translation of non-canonical open reading frames (ncORFs) has been observed across human cell types and disease states, with major implications for proteomics, genomics, and clinical science. However, the impact of ncORFs has been limited by the absence of a large-scale understanding of their contribution to the human proteome. Here, we report the collaborative efforts of stakeholders in proteomics, immunopeptidomics, Ribo-seq ORF discovery, and gene annotation, to produce a consensus landscape of protein-level evidence for ncORFs. We show that at least 25% of a set of 7,264 ncORFs give rise to translated gene products, yielding over 3,000 peptides in a pan-proteome analysis encompassing 3.8 billion mass spectra from 95,520 experiments. With these data, we developed an annotation framework for ncORFs and created public tools for researchers through GENCODE and PeptideAtlas. This work will provide a platform to advance ncORF-derived proteins in biomedical discovery and, beyond humans, diverse animals and plants where ncORFs are similarly observed.
    DOI:  https://doi.org/10.1101/2024.09.09.612016
  5. Proteomes. 2024 Sep 13. pii: 26. [Epub ahead of print]12(3):
    Multi-Omic Approaches in Cancer-Related Micropeptide Identification.
    Katarina Vrbnjak, Raj Nayan Sewduth.
      Despite the advances in modern cancer therapy, malignant diseases are still a leading cause of morbidity and mortality worldwide. Conventional treatment methods frequently lead to side effects and drug resistance in patients, highlighting the need for novel therapeutic approaches. Recent findings have identified the existence of non-canonical micropeptides, an additional layer of the proteome complexity, also called the microproteome. These small peptides are a promising class of therapeutic agents with the potential to address the limitations of current cancer treatments. The microproteome is encoded by regions of the genome historically annotated as non-coding, and its existence has been revealed thanks to recent advances in proteomic and bioinformatic technology, which dramatically improved the understanding of proteome complexity. Micropeptides have been shown to be biologically active in several cancer types, indicating their therapeutic role. Furthermore, they are characterized by low toxicity and high target specificity, demonstrating their potential for the development of better tolerated drugs. In this review, we survey the current landscape of known micropeptides with a role in cancer progression or treatment, discuss their potential as anticancer agents, and describe the methodological challenges facing the proteome field of research.
    Keywords:  SEPs; cancer; micropeptides; microproteome complexity; multi-omics; non-canonical peptides; peptide drugs
    DOI:  https://doi.org/10.3390/proteomes12030026
  6. Nucleic Acids Res. 2024 Sep 25. pii: gkae808. [Epub ahead of print]
    RPFdb v3.0: an enhanced repository for ribosome profiling data and related content.
    Yan Wang, Yuewen Tang, Zhi Xie, Hongwei Wang.
      RPFdb (http://www.rpfdb.org or http://sysbio.gzzoc.com/rpfdb/) is a comprehensive repository dedicated to hosting ribosome profiling (Ribo-seq) data and related content. Herein, we present RPFdb v3.0, a significant update featuring expanded data content and improved functionality. Key enhancements include (i) increased data coverage, now encompassing 5018 Ribo-seq datasets and 2343 matched RNA-seq datasets from 496 studies across 34 species; (ii) implementation of translation efficiency, combining Ribo-seq and RNA-seq data to provide gene-specific translation efficiency; (iii) addition of pausing score, facilitating the identification of condition-specific triplet amino acid motifs with enhanced ribosome enrichment; (iv) refinement of open reading frame (ORF) annotation, leveraging RibORF v2.0 for more sensitive detection of actively translated ORFs; (v) introduction of a resource hub, curating advances in translatome sequencing techniques and data analytics tools to support a panoramic overview of the field; and (vi) redesigned web interface, providing intuitive navigation with dedicated pages for streamlined data retrieval, comparison and visualization. These enhancements make RPFdb a more powerful and user-friendly resource for researchers in the field of translatomics. The database is freely accessible and regularly updated to ensure its continued relevance to the scientific community.
    DOI:  https://doi.org/10.1093/nar/gkae808
  7. Nat Commun. 2024 Sep 27. 15(1): 8381
    The microprotein HDSP promotes gastric cancer progression through activating the MECOM-SPINK1-EGFR signaling axis.
    Yuli Chen, Qiuhui Li, Xiang Yu, Lu Lu, Zihan Zhou, Mingjie Li, Rui Xia, Xiongkang Gan, Yanming Hu, Guoqing Guo, Jiahao Guo, Hanyang Li, Qiunuo Li, Yanwen Liu, Xianghua Liu, Ming Sun.
      The presence of noncanonical open reading frames within lncRNAs (long non-coding RNAs) suggests their potential for translation, yielding various functional peptides or proteins. However, the existence and specific roles of these products in gastric cancer remain largely unclear. Here we identify the HOXA10-HOXA9-derived small protein (HDSP) in gastric cancer through comprehensive analysis and experimental validation, including mass spectrometry and western blotting. HDSP exhibits high expression and oncogenic roles in gastric cancer. Mechanistically, HDSP blocks TRIM25-mediated ubiquitination and degradation by interacting with MECOM, leading to MECOM accumulation and enhanced SPINK1 transcription-a gene promoting cancer via the EGFR signaling pathway. Furthermore, MECOM fosters HOXA10-HOXA9 transcription, establishing a feedback loop activating SPINK1-EGFR signaling. HDSP knockdown inhibits tumor growth in a PDX (patient-derived xenograft) model, and infusion of an artificially synthesized HDSP peptide as a neoantigen enhances immune cell-mediated anti-tumor efficacy against gastric cancer in vitro and in vivo. These findings propose HDSP as a potential therapeutic target or neoantigen candidate for gastric cancer treatment.
    DOI:  https://doi.org/10.1038/s41467-024-50986-7
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