bims-micpro Biomed News
on Discovery and characterization of microproteins
Issue of 2025–03–23
seven papers selected by
Thomas Farid Martínez, University of California, Irvine
  1. Mutational constraint analysis workflow for overlapping short open reading frames and genomic neighbors.
  2. Enhancing the annotation of small ORF-altering variants using MORFEE: introducing MORFEEdb, a comprehensive catalog of SNVs affecting upstream ORFs in human 5'UTRs.
  3. A plant peptide with dual activity against multidrug-resistant bacterial and fungal pathogens.
  4. Sertm2 is a conserved micropeptide that promotes GDNF-mediated motor neuron subtype specification.
  5. Mind the gap: Intergenic regions in bacteria encode numerous small proteins.
  6. A cardiac fibroblast-enriched micropeptide regulates inflammation in ischemia/reperfusion injury.
  7. Mitoregulin, a tiny protein at the crossroads of mitochondrial functioning, stress, and disease.
  1. BMC Genomics. 2025 Mar 14. 26(1): 254
    Mutational constraint analysis workflow for overlapping short open reading frames and genomic neighbors.
    Martin Danner, Matthias Begemann, Florian Kraft, Miriam Elbracht, Ingo Kurth, Jeremias Krause.
      Understanding the dark genome is a priority task following the complete sequencing of the human genome. Short open reading frames (sORFs) are a group of largely unexplored elements of the dark genome with the potential for being translated into microproteins. The definitive number of coding and regulatory sORFs is not known, however they could account for up to 1-2% of the human genome. This corresponds to an order of magnitude in the range of canonical coding genes. For a few sORFs a clinical relevance has already been demonstrated, but for the majority of potential sORFs the biological function remains unclear. A major limitation in predicting their disease relevance using large-scale genomic data is the fact that no population-level constraint metrics for genetic variants in sORFs are yet available. To overcome this, we used the recently released gnomAD 4.0 dataset and analyzed the constraint of a consensus set of sORFs and their genomic neighbors. We demonstrate that sORFs are mostly embedded into a moderately constrained genomic context, but within the gencode dataset we identified a subset of highly constrained sORFs comparable to highly constrained canonical genes.
    Keywords:  Computational genomics; Population genomics; Short open reading frames
    DOI:  https://doi.org/10.1186/s12864-025-11444-w
  2. NAR Genom Bioinform. 2025 Mar;7(1): lqaf017
    Enhancing the annotation of small ORF-altering variants using MORFEE: introducing MORFEEdb, a comprehensive catalog of SNVs affecting upstream ORFs in human 5'UTRs.
    Caroline Meguerditchian, David Baux, Thomas E Ludwig, Emmanuelle Genin, David-Alexandre Trégouët, Omar Soukarieh.
      Non-canonical small open reading frames (sORFs) are among the main regulators of gene expression. The most studied of these are upstream ORFs (upORFs) located in the 5'-untranslated region (UTR) of coding genes. Internal ORFs (intORFs) in the coding sequence and downstream ORFs (dORFs) in the 3'UTR have received less attention. Different bioinformatics tools permit the prediction of single nucleotide variants (SNVs) altering upORFs, mainly those creating AUGs or deleting stop codons, but no tool predicts variants altering non-canonical translation initiation sites and those altering intORFs or dORFs. We propose an upgrade of our MORFEE bioinformatics tool to identify SNVs that may alter all types of sORFs in coding transcripts from a VCF file. Moreover, we generate an exhaustive catalog, named MORFEEdb, reporting all possible SNVs altering existing upORFs or creating new ones in human transcripts, and provide an R script for visualizing the results. MORFEEdb has been implemented in the public platform Mobidetails. Finally, the annotation of ClinVar variants with MORFEE reveals that > 45% of UTR-SNVs can alter upORFs or dORFs. In conclusion, MORFEE and MORFEEdb have the potential to improve the molecular diagnosis of rare human diseases and to facilitate the identification of functional variants from genome-wide association studies of complex traits.
    DOI:  https://doi.org/10.1093/nargab/lqaf017
  3. Sci Adv. 2025 Mar 21. 11(12): eadt8239
    A plant peptide with dual activity against multidrug-resistant bacterial and fungal pathogens.
    Xueyan Chen, Meirong Song, Lei Tian, Xinxin Shan, Changsi Mao, Minghui Chen, Jiaqi Zhao, Abdul Sami, Haoqiang Yin, Usman Ali, Jiawei Shi, Hehuan Li, Yuqian Zhang, Jinghua Zhang, Shunxi Wang, Chun-Lin Shi, Yanhui Chen, Xiang-Dang Du, Kui Zhu, Liuji Wu.
      Multidrug-resistant (MDR) bacteria pose a major threat to public health, and additional sources of antibacterial candidates are urgently needed. Noncanonical peptides (NCPs), derived from noncanonical small open reading frames, represent small biological molecules with important roles in biology. However, the antibacterial activity of NCPs remains largely unknown. Here, we discovered a plant-derived noncanonical antibacterial peptide (NCBP1) against both Gram-positive and Gram-negative bacteria. NCBP1 is composed of 11 amino acid residues with cationic surface potential and favorable safety and stability. Mechanistic studies revealed that NCBP1 displayed antibacterial activity by targeting phosphatidylglycerol and cardiolipin in bacterial membrane, resulting in membrane damage and dysfunction. Notably, NCBP1 showed promising efficacy in mice. Furthermore, NCBP1 effectively inhibited the growth of plant fungal pathogens and enhanced disease resistance in maize. Our results demonstrate the unexplored antimicrobial potential of plant-derived NCPs and provide an accessible source for the discovery of antimicrobial substances against MDR bacterial and fungal pathogens.
    DOI:  https://doi.org/10.1126/sciadv.adt8239
  4. EMBO Rep. 2025 Mar 19.
    Sertm2 is a conserved micropeptide that promotes GDNF-mediated motor neuron subtype specification.
    Fang-Yu Hsu, Ya-Ping Yen, Hung-Chi Fan, Mien Chang, Jun-An Chen.
      Small open-reading frame-encoded micropeptides within long noncoding RNAs (lncRNAs) are often overlooked due to their small size and low abundance. However, emerging evidence links these micropeptides to various biological pathways, though their roles in neural development and neurodegeneration remain unclear. Here, we investigate the function of murine micropeptide Sertm2, encoded by the lncRNA A730046J19Rik, during spinal motor neuron (MN) development. Sertm2 is predicted to be a conserved transmembrane protein found in both mouse and human, with subcellular analysis revealing that it is enriched in the cytoplasm and neurites. By generating C terminally Flag-tagged Sertm2 and expressing it from the A730046J19Rik locus, we demonstrate that the Sertm2 micropeptide localizes in spinal MNs in mice. The GDNF signaling-induced Etv4+ motor pool is impaired in Sertm2 knockout mice, which display motor nerve arborization defects that culminate in impaired motor coordination and muscle weakness. Similarly, human SERTM2 knockout iPSC-derived MNs also display reduced ETV4+ motor pools, highlighting that Sertm2 is a novel, evolutionarily conserved micropeptide essential for maintaining GDNF-induced MN subtype identity.
    Keywords:  Etv4; GDNF; Long Noncoding RNA; Micropeptide; Motor Neurons
    DOI:  https://doi.org/10.1038/s44319-025-00400-0
  5. Mol Cell. 2025 Mar 20. pii: S1097-2765(25)00149-2. [Epub ahead of print]85(6): 1046-1048
    Mind the gap: Intergenic regions in bacteria encode numerous small proteins.
    Jordan D Lin, Ami S Bhatt.
      In a recent issue of Molecular Cell, Fesenko et al.1 report a systematic investigation of intergenic regions within Enterobacteriaceae, shedding light on a vast, unexplored microprotein landscape that has been overlooked in well-characterized bacterial genomes.
    DOI:  https://doi.org/10.1016/j.molcel.2025.02.018
  6. JCI Insight. 2025 Mar 20. pii: e187848. [Epub ahead of print]
    A cardiac fibroblast-enriched micropeptide regulates inflammation in ischemia/reperfusion injury.
    Youchen Yan, Tingting Zhang, Xin He, Tailai Du, Gang Dai, Xingfeng Xu, Zhuohui Chen, Jialing Wu, Huimin Zhou, Yazhi Peng, Yan Li, Chen Liu, Xinxue Liao, Yugang Dong, Jing-Song Ou, Zhan-Peng Huang.
      Inflammation is a critical pathological process in myocardial infarction. Although immunosuppressive therapies can mitigate inflammatory responses and improve outcomes in myocardial infarction, they also increase the risk of infections. Identifying novel regulators of local cardiac inflammation could provide safer therapeutic targets for myocardial ischemia/reperfusion injury. In this study, we identified a previously unknown micropeptide, which we named Inflammation Associated MicroPeptide (IAMP). IAMP is predominantly expressed in cardiac fibroblasts, and its expression is closely associated with cardiac inflammation. Down-regulation of IAMP promotes, whereas its overexpression prevents, the transformation of cardiac fibroblasts into a more inflammatory phenotype under stressed/stimulated conditions, as evidenced by changes in the expression and secretion of pro-inflammatory cytokines. Consequently, loss of IAMP function leads to uncontrolled inflammation and worsens cardiac injury following ischemia/reperfusion surgery. Mechanistically, IAMP promotes the degradation of HIF-1α by interacting with its stabilizing partner HSP90, and thus suppresses the transcription of pro-inflammatory genes downstream of HIF-1α. This study underscores the significance of fibroblast-mediated inflammation in cardiac ischemia/reperfusion injury and highlights the therapeutic potential of targeting micropeptides for myocardial infarction.
    Keywords:  Cardiology; Cardiovascular disease; Cell biology
    DOI:  https://doi.org/10.1172/jci.insight.187848
  7. Front Cell Dev Biol. 2025 ;13 1545359
    Mitoregulin, a tiny protein at the crossroads of mitochondrial functioning, stress, and disease.
    Petr Sergiev, Olga Averina, Julia Golubeva, Mikhail Vyssokikh, Olga Dontsova.
      Mitoregulin (Mtln) is a small mitochondrial protein that was only recently identified. Despite this, a substantial number of studies on its function have already been published. Although sometimes contradictory, these studies have revealed the localization of Mtln, its protein and lipid partners, and its role in lipid homeostasis, energy metabolism, oxidative stress, and other aspects of mitochondrial functioning. Moreover, research using knockout and transgenic mouse models has revealed the important role of Mtln in mammalian physiology. Metabolic changes, along with muscle, kidney, and fat-related phenotypes, have been linked to Mtln dysfunction. In this review, we summarize a comprehensive set of published data on Mtln. While controversies remain, we seek to offer a unified view of its functions, spanning molecular mechanisms to organism-level effects.
    Keywords:  Mtln; cardiolipin; membrane; mitochondria; respiration; small peptide
    DOI:  https://doi.org/10.3389/fcell.2025.1545359
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