bims-micpro Biomed News
on Discovery and characterization of microproteins
Issue of 2023‒12‒10
five papers selected by
Thomas Farid Martínez, University of California, Irvine

  1. PLoS Biol. 2023 Dec 04. 21(12): e3002409
      Ribosome profiling experiments indicate pervasive translation of short open reading frames (ORFs) outside of annotated protein-coding genes. However, shotgun mass spectrometry (MS) experiments typically detect only a small fraction of the predicted protein products of this noncanonical translation. The rarity of detection could indicate that most predicted noncanonical proteins are rapidly degraded and not present in the cell; alternatively, it could reflect technical limitations. Here, we leveraged recent advances in ribosome profiling and MS to investigate the factors limiting detection of noncanonical proteins in yeast. We show that the low detection rate of noncanonical ORF products can largely be explained by small size and low translation levels and does not indicate that they are unstable or biologically insignificant. In particular, proteins encoded by evolutionarily young genes, including those with well-characterized biological roles, are too short and too lowly expressed to be detected by shotgun MS at current detection sensitivities. Additionally, we find that decoy biases can give misleading estimates of noncanonical protein false discovery rates, potentially leading to false detections. After accounting for these issues, we found strong evidence for 4 noncanonical proteins in MS data, which were also supported by evolution and translation data. These results illustrate the power of MS to validate unannotated genes predicted by ribosome profiling, but also its substantial limitations in finding many biologically relevant lowly expressed proteins.
  2. J Assist Reprod Genet. 2023 Dec 05.
      BACKGROUND: Endometrial receptivity (ER), a pivotal event for successful embryo implantation, refers to the capacity of endometrium to allow the adhesion of the trophectoderm of the blastocyst to endometrial cells. In this paper, we set to elucidate whether the peptides encoded by lncRNAs could influence trophoblast cells' adhesion to endometrial cells.METHODS: WGCNA construction and bioinformatics were used to find out the ER-related lncRNAs with coding potential. Protein analysis was done by immunoblotting and immunofluorescence (IF) microscopy. CCK-8 and Calcein-AM/PI double staining assays were employed to evaluate cell viability. The effect of the peptide on trophoblast spheroids' adhesion to endometrial cells was evaluated. The RNA sequencing (RNA-seq) analysis was applied to identify downstream molecular processes.
    RESULTS: lncRNA LINC00339 was found to be related to ER development and it had been predicted to have protein-coding potential. LINC00339 had high occupancy of ribosomes and was confirmed to encode a 49-aa peptide (named LINC00339-205-49aa). LINC00339-205-49aa could promote the attachment of JAR trophoblast spheroids to Ishikawa endometrial cells in vitro. LINC00339-205-49aa also upregulated the expression of E-cadherin in Ishikawa cells. Mechanistically, MAPK and PI3K-Akt signaling pathways were involved in the modulation of LINC00339-205-49aa, which were activated by LINC00339-205-49aa in Ishikawa cells.
    CONCLUSION: These data demonstrate that a previously uncharacterized peptide encoded by lncRNA LINC00339 has the ability to enhance JAR trophoblast spheroids' adhesion to Ishikawa endometrial cells, highlighting a new opportunity for the development of drugs to improve ER.
    Keywords:  Endometrial cells; Endometrial receptivity; Trophoblast cells; lncRNA-encoded peptide
  3. Cancer Lett. 2023 Dec 04. pii: S0304-3835(23)00466-4. [Epub ahead of print] 216515
      Bladder cancer (BC) is a common malignancy in males, and currently lacks ideal therapeutic approaches. Exploring emerging therapeutic targets from the perspective of endogenous peptides to improve the prognosis of bladder cancer patients holds promise. In this study, we have identified CTSGDP-13, a novel endogenous peptide, which demonstrates potential anti-cancer effects in bladder cancer. Our findings reveal that CTSGDP-13 can promote ferroptosis in BC cells, both in vitro and in vivo, leading to the inhibition of BC progression. Furthermore, we have identified TRIM25 as a downstream regulatory target of CTSGDP-13. The expression of TRIM25 is significantly upregulated in BC, and its inhibition of ferroptosis promotes BC progression. Mechanistic studies have shown that CTSGDP-13 promotes the ubiquitination and subsequent degradation of TRIM25 by disrupting its interaction with the deubiquitinase USP7. Further investigations indicate that CTSGDP-13 promotes ferroptosis in BC by regulating the USP7/TRIM25/KEAP1/NRF2 axis. The elucidation of the functional mechanisms of natural CTSGDP-13 and TRIM25 holds promise in providing valuable therapeutic targets for BC diagnosis and treatment.
    Keywords:  Cancer; Ferroptosis; TRIM25; USP7; Ubiquitination
  4. J Zhejiang Univ Sci B. 2023 Dec 15. pii: 1673-1581(2023)12-1106-17. [Epub ahead of print]24(12): 1106-1122
      With the development of modern sequencing techniques and bioinformatics, genomes that were once thought to be noncoding have been found to encode abundant functional micropeptides (miPs), a kind of small polypeptides. Although miPs are difficult to analyze and identify, a number of studies have begun to focus on them. More and more miPs have been revealed as essential for energy metabolism homeostasis, immune regulation, and tumor growth and development. Many reports have shown that miPs are especially essential for regulating glucose and lipid metabolism and regulating mitochondrial function. MiPs are also involved in the progression of related diseases. This paper reviews the sources and identification of miPs, as well as the functional significance of miPs for metabolism-related diseases, with the aim of revealing their potential clinical applications.
    Keywords:  Energy metabolism; Micropeptides; Mitochondria; Noncoding RNA (ncRNA); Small open reading frame (sORF)
  5. iScience. 2023 Dec 15. 26(12): 107985
      Tissue resident macrophages are largely of embryonic (fetal liver) origin and long-lived, while bone marrow-derived macrophages (BMDM) are recruited following an acute perturbation, such as hypoxia in the setting of myocardial ischemia. Prior transcriptome analyses identified BMDM and fetal liver-derived macrophage (FLDM) differences at the RNA expression level. Posttranscriptional regulation determining mRNA stability and translation rate may override transcriptional signals in response to hypoxia. We profiled differentially regulated BMDM and FLDM transcripts in response to hypoxia at the level of mRNA translation. Using a translating ribosome affinity purification (TRAP) assay and RNA-seq, we identified non-overlapping transcripts with increased translation rate in BMDM (Ly6e, vimentin, PF4) and FLDM (Ccl7, Ccl2) after hypoxia. We further identified hypoxia-induced transcripts within these subsets that are regulated by the RNA-binding protein HuR. These findings define translational differences in macrophage subset gene expression programs, highlighting potential therapeutic targets in ischemic myocardium.
    Keywords:  Biological sciences; Cell biology; Immunology; Molecular biology