bims-micpro Biomed News
on Discovery and characterization of microproteins
Issue of 2024–12–29
seven papers selected by
Thomas Farid Martínez, University of California, Irvine
  1. [Human eRF1 Translation Regulation].
  2. [Revision of Functionally Relevant and Widely Expressed Long Non-Coding RNAs].
  3. From non-coding to coding: The importance of long non-coding RNA translation in de novo gene birth.
  4. Endurance training enhances skeletal muscle mitochondrial respiration by promoting MOTS-c secretion.
  5. Dilated cardiomyopathy variant R14del increases phospholamban pentamer stability, blunting dynamic regulation of calcium.
  6. More than 2,500 coding genes in the human reference gene set still have unsettled status.
  7. A small peptide miPEP172b encoded by primary transcript of miR172b regulates salt tolerance in rice.
  1. Mol Biol (Mosk). 2024 Jul-Aug;58(4):58(4): 627-637
    [Human eRF1 Translation Regulation].
    A V Shuvalov, A A Klishin, N S Biziaev, E Y Shuvalova, E Z Alkalaeva.
      Eukaryotic translation release factor eRF1 is an important cellular protein that plays a key role in translation termination, nonsense-mediated mRNA decay (NMD), and readthrough of stop codons. The amount of eRF1 in the cell influences all these processes. The mechanism of regulation of eRF1 translation through an autoregulatory NMD-dependent expression circuit has been described for plants and fungi, but the mechanisms of regulation of human eRF1 translation have not yet been studied. Using reporter constructs, we studied the effect of eRF1 mRNA elements on its translation in cell-free translation systems and HEK293 cell culture. Our data indicate the absence of an NMD-dependent autoregulatory circuit for human eRF1 expression. We found that the translation of the eRF1 coding sequence is most strongly influenced by the 5' untranslated region of eRF1 mRNA and the start codon of the upstream open reading frame. According to the transcription start database, eRF1 mRNA is characterized by high heterogeneity of the transcription start and a variable 5' untranslated region in length. In addition, the start codon of the CDS in eRF1 mRNA is located within the known translational regulator of short 5' untranslated regions (TISU), which also stimulates mRNA transcription of genes with high transcription start heterogeneity. We hypothesize that regulation of human eRF1 synthesis occurs at both the transcriptional and translational levels. At the transcription level, the length of the eRF1 5' untranslated region and the number of the upstream open reading frames in it are regulated. This regulation in turn, regulates the production of eRF1 at the translation level.
    Keywords:  3'-UTR; 5'-UTR; eRF1; mRNA; translation
    DOI:  https://doi.org/10.31857/S0026898424040091, EDN: IMNJKL
  2. Mol Biol (Mosk). 2024 May-Jun;58(3):58(3): 493-506
    [Revision of Functionally Relevant and Widely Expressed Long Non-Coding RNAs].
    D Konina, M Skoblov.
      Long non-coding RNAs (lncRNAs) are involved in many cellular processes while displaying high tissue specificity. In contrast, protein-coding genes, including the category of housekeeping ones, exhibit broad expression patterns. The aim of this study was to highlight the functional importance of widely expressed lncRNAs. We analyzed experimental data from cell-growth screen of lncRNA loci in human cells, which allowed us to identify 18 lncRNA hits. Notably, these lncRNAs were not only widely expressed in most human tissues, but also played functional roles within them. Detail investigation revealed them encompass a variety of molecular functions, from cardiomyocyte damage controlling to macrophage class switching. Interestingly, experimental data highlighted the fact that a significant part of these lncRNAs encoded small but functional polypeptides. A set of lncRNAs, NEAT1, SNHG1, SNHG7, SNHG12, SNHG15, SNHG16, MIR17HG, LINC00680, LINC00263 and LINC00339, that were highly likely to be translated into small polypeptides was identified. Additionally, for EPB41L4A-AS1, CRNDE, SNHG6, LINC00493, and LINC01420, a dual function associated with both the RNA sequences and small proteins they encoded was established.
    Keywords:  CRISPRi; long non-coding RNA; short open reading frame
    DOI:  https://doi.org/10.31857/S0026898424030137, EDN: JBZHXL
  3. Biochim Biophys Acta Gen Subj. 2024 Dec 19. pii: S0304-4165(24)00190-9. [Epub ahead of print] 130747
    From non-coding to coding: The importance of long non-coding RNA translation in de novo gene birth.
    Taichi Shiraishi, Akinobu Matsumoto.
      Recent emerging evidence demonstrates that some long non-coding RNAs (lncRNAs) can indeed be translated into functional polypeptides. These discoveries are pivotal for understanding de novo gene birth, the process by which new genes evolve from previously non-genic regions. In this review, we first introduce key methods, such as Ribo-seq and translation initiation site detection by translation complex analysis, for identifying coding sequences within lncRNAs and highlight examples of functional polypeptides derived from lncRNAs across species. These polypeptides play essential roles in maintaining cellular homeostasis and contribute to pathological processes, including cancer. However, because not all lncRNA-derived polypeptides appear to be functional, these lncRNAs may act as gene reservoirs. We also discuss how lncRNAs change their intracellular localization, how lncRNA-derived polypeptides evade immune surveillance, and how they gradually evolve into typical coding RNAs, providing evidence for the evolutionary model of de novo gene birth.
    Keywords:  De novo gene birth; Long non-coding RNA; Polypeptide; Ribo-seq; Translation; Translation initiation site detection by translation complex analysis
    DOI:  https://doi.org/10.1016/j.bbagen.2024.130747
  4. Free Radic Biol Med. 2024 Dec 18. pii: S0891-5849(24)01147-X. [Epub ahead of print]227 619-628
    Endurance training enhances skeletal muscle mitochondrial respiration by promoting MOTS-c secretion.
    Yiwei Feng, Zhijian Rao, Xu Tian, Yi Hu, Liantian Yue, Yifan Meng, Qiuling Zhong, Wei Chen, Wenlong Xu, Haoran Li, Yingjia Hu, Rengfei Shi.
      The mitochondrial open reading frame of 12S rRNA-c (MOTS-c) is a biologically active mitochondria-derived peptide. However, the relationship between MOTS-c, skeletal muscle mitochondrial function, and endurance exercise adaptations is unknown. Here, we tested indices such as maximal oxygen uptake and serum MOTS-c levels in marathon runners and sedentary subjects. In addition, we tested aerobic exercise capacity, skeletal muscle mitochondrial respiration rate, and serum MOTS-c levels in mice subjected to long-term endurance training groups and sedentary groups. Our results indicated a close association between serum MOTS-c levels and aerobic exercise capacity. Circulating MOTS-c levels are expected to be an important indicator for predicting aerobic exercise capacity and assessing body fat status, endurance training load, and physical function. More importantly, we found that endurance training may enhance the mitochondrial respiratory function of skeletal muscle by promoting the secretion of MOTS-c and activating the AMPK/PGC-1α pathway.
    Keywords:  Exercise; Mitochondria; Mitochondrial-derived peptides; Skeletal muscle; The mitochondrial open reading frame of the 12S ribosomal RNA type-c (MOTS-C)
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.12.038
  5. J Biol Chem. 2024 Dec 20. pii: S0021-9258(24)02620-6. [Epub ahead of print] 108118
    Dilated cardiomyopathy variant R14del increases phospholamban pentamer stability, blunting dynamic regulation of calcium.
    Sean R Cleary, Allen C T Teng, Audrey Deyawe Kongmeneck, Xuan Fang, Taylor A Phillips, Ellen E Cho, Rhys A Smith, Patryk Karkut, Catherine A Makarewich, Peter M Kekenes-Huskey, Anthony O Gramolini, Seth L Robia.
      The sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) is a membrane transporter that creates and maintains intracellular Ca2+ stores. In the heart, SERCA is regulated by an inhibitory interaction with the monomeric form of the transmembrane micropeptide phospholamban (PLB). PLB also forms avid homo-pentamers, and dynamic exchange of PLB between pentamers and SERCA is an important determinant of cardiac responsiveness to exercise. Here, we investigated two naturally occurring pathogenic variants of PLB: a cysteine substitution of Arg9 (R9C) and an in-frame deletion of Arg14 (R14del). Both variants are associated with dilated cardiomyopathy. We previously showed that the R9C mutation causes disulfide crosslinking and hyperstabilization of pentamers. While the pathogenic mechanism of R14del is unclear, we hypothesized this mutation may also alter pentamer stability. Immunoblots revealed a significantly increased pentamer:monomer ratio for R14del-PLB compared to WT-PLB. We quantified homo-oligomerization and SERCA-binding in live cells using fluorescence resonance energy transfer (FRET) microscopy. R14del-PLB showed increased affinity for homo-oligomerization and decreased binding affinity for SERCA compared to WT. The data suggest that, like R9C, the R14del mutation stabilizes PLB in pentamers, decreasing its ability to regulate SERCA. The R14del mutation reduces the rate of PLB unbinding from pentamers after transient elevations of Ca2+, limiting the recovery of PLB-SERCA complexes. A computational model predicted that hyperstabilization of PLB pentamers by R14del impairs the ability of cardiac Ca2+ handling to respond to changing heart rates between rest and exercise. We postulate that impaired responsiveness to physiological stress contributes to arrhythmogenesis in human carriers of the R14del mutation.
    Keywords:  Calcium Transporter; Cardiac Calcium Handling; Dilated Cardiomyopathy; FRET microscopy; Ion-motive ATPase; Micropeptides; Microproteins; R14del variant of phospholamban; Regulins; SERCA pump; protein-protein binding dynamics
    DOI:  https://doi.org/10.1016/j.jbc.2024.108118
  6. bioRxiv. 2024 Dec 09. pii: 2024.12.05.626965. [Epub ahead of print]
    More than 2,500 coding genes in the human reference gene set still have unsettled status.
    Miguel Maquedano, Daniel Cerdán-Vélez, Michael L Tress.
      In 2018 we analysed the three main repositories for the human proteome, Ensembl/GENCODE, RefSeq and UniProtKB. They disagreed on the coding status of one of every eight annotated coding genes. The analysis inspired bilateral collaborations between annotation groups. Here we have repeated our analysis with updated versions of the three reference coding gene sets. Superficially, little appears to have changed. Although there are slightly fewer genes predicted as coding overall, the three groups still disagree on the status of 2,606 annotated genes. However, a comparison without read-through genes and immunoglobulin fragments shows that the three reference sets have merged or reclassified more than 700 genes since the last analysis and that just 0.6% of Ensembl/GENCODE coding genes are not also annotated by the other two reference sets. We used eight features indicative of non-coding genes to examine the 21,873 coding genes annotated across the three reference sets. We found that more than 2,000 had one or more potential non-coding features. While some of these genes will be protein coding, we believe that most are likely to be non-coding genes or pseudogenes. Our results suggest that annotators still vastly overestimate the number of true coding genes.
    DOI:  https://doi.org/10.1101/2024.12.05.626965
  7. Plant Physiol Biochem. 2024 Dec 24. pii: S0981-9428(24)01110-0. [Epub ahead of print]219 109442
    A small peptide miPEP172b encoded by primary transcript of miR172b regulates salt tolerance in rice.
    Long Lu, Yuan Wang, Zecong Huang, Shunjiao Qiu, Jie Lin, Yiran Feng, Yuke Zhang, Xinyu Chen, Siwen Xie, Yinuo Ma, Yuanyuan Song, Rensen Zeng.
      Recent studies have demonstrated that the primary transcript of miRNAs (pri-miRNAs) are able to encode small peptides influencing plant growth and development, as well as responses to various environmental cues. However, their role in plant responses to salt stress is not fully comprehended. Here, we characterized a short peptide encoded by miR172b (miPEP172b) in rice (Oryza sativa L.). By applying synthetic miPEP172b, we observed a significant increase in miR172b abundance and a decrease in the expression of its target gene IDS1. Consequently, plants treated with miPEP172b exhibited enhanced tolerance to salinity stress. Furthermore, we found that miPEP172b was efficiently absorbed by roots and transported to the aerial parts of the plant, thus conferring salt tolerance in the aboveground organs. Overexpression of miPEP172b resulted in reduced levels of reactive oxygen species (ROS), leading to improved performance of rice seedlings under salinity conditions. This was consistent with the observations in miR172-overexpressing plants. Conversely, miPEP172b mutants showed increased sensitivity to salt stress. Further analysis revealed that miPEP172b-miR172-IDS1 improved rice salt tolerance by integrating the ROS scavenging pathway and plant hormone signaling. Our findings highlight the significant role of miPEP172b in regulating miR172 activity and salt tolerance, providing a useful agent for improving crop salt tolerance.
    Keywords:  ROS; Rice; Salt stress; miR172; miRNA-encoded peptide
    DOI:  https://doi.org/10.1016/j.plaphy.2024.109442
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