bims-micpro Biomed News
on Discovery and characterization of microproteins
Issue of 2025–02–02
five papers selected by
Thomas Farid Martínez, University of California, Irvine
  1. The transcriptional and translational landscape of HCoV-OC43 infection.
  2. A novel uORF regulates folliculin to promote cell growth and lysosomal biogenesis during cardiac stress.
  3. Principles, challenges, and advances in ribosome profiling: from bulk to low-input and single-cell analysis.
  4. The cryptic lncRNA-encoded microprotein TPM3P9 drives oncogenic RNA splicing and tumorigenesis.
  5. Integrative multi-omics analysis reveals the translational landscape of the plant-parasitic nematode Meloidogyne incognita.
  1. PLoS Pathog. 2025 Jan;21(1): e1012831
    The transcriptional and translational landscape of HCoV-OC43 infection.
    Stefan Bresson, Emanuela Sani, Alicja Armatowska, Charles Dixon, David Tollervey.
      The coronavirus HCoV-OC43 circulates continuously in the human population and is a frequent cause of the common cold. Here, we generated a high-resolution atlas of the transcriptional and translational landscape of OC43 during a time course following infection of human lung fibroblasts. Using ribosome profiling, we quantified the relative expression of the canonical open reading frames (ORFs) and identified previously unannotated ORFs. These included several potential short upstream ORFs and a putative ORF nested inside the M gene. In parallel, we analyzed the cellular response to infection. Endoplasmic reticulum (ER) stress response genes were transcriptionally and translationally induced beginning 12 and 18 hours post infection, respectively. By contrast, conventional antiviral genes mostly remained quiescent. At the same time points, we observed accumulation and increased translation of noncoding transcripts normally targeted by nonsense mediated decay (NMD), suggesting NMD is suppressed during the course of infection. This work provides resources for deeper understanding of OC43 gene expression and the cellular responses during infection.
    DOI:  https://doi.org/10.1371/journal.ppat.1012831
  2. Sci Rep. 2025 Jan 27. 15(1): 3319
    A novel uORF regulates folliculin to promote cell growth and lysosomal biogenesis during cardiac stress.
    Maja Bencun, Laura Spreyer, Etienne Boileau, Jessica Eschenbach, Norbert Frey, Christoph Dieterich, Mirko Völkers.
      Pathological cardiac remodeling is a maladaptive response that leads to changes in the size, structure, and function of the heart. These changes occur due to an acute or chronic stress on the heart and involve a complex interplay of hemodynamic, neurohormonal and molecular factors. As a critical regulator of cell growth, protein synthesis and autophagy mechanistic target of rapamycin complex 1 (mTORC1) is an important mediator of pathological cardiac remodeling. The tumor suppressor folliculin (FLCN) is part of the network regulating non-canonical mTORC1 activity. FLCN activates mTORC1 by functioning as a guanosine triphosphatase activating protein (GAP). Our work has identified a regulatory upstream open reading frame (uORF) localized in the 5'UTR of the FLCN mRNA. These small genetic elements are important regulators of protein expression. They are particularly important for the regulation of stress-responsive protein synthesis. We have studied the relevance of the FLCN uORF in the regulation of FLCN translation. We show that FLCN downregulation through the uORF is linked to cardiomyocyte growth and increased lysosomal activity. In summary, we have identified uORF-mediated control of RNA translation as another layer of regulation in the complex molecular network controlling cardiomyocyte hypertrophy.
    Keywords:  Folliculin; Hypertrophic growth; Lysosome; TFEB; Translation; Upstream open reading frame
    DOI:  https://doi.org/10.1038/s41598-025-87107-3
  3. Adv Biotechnol (Singap). 2023 Dec 01. 1(4): 6
    Principles, challenges, and advances in ribosome profiling: from bulk to low-input and single-cell analysis.
    Qiuyi Wang, Yuanhui Mao.
      Ribosome profiling has revolutionized our understanding of gene expression regulation by providing a snapshot of global translation in vivo. This powerful technique enables the investigation of the dynamics of translation initiation, elongation, and termination, and has provided insights into the regulation of protein synthesis under various conditions. Despite its widespread adoption, challenges persist in obtaining high-quality ribosome profiling data. In this review, we discuss the fundamental principles of ribosome profiling and related methodologies, including selective ribosome profiling and translation complex profiling. We also delve into quality control to assess the reliability of ribosome profiling datasets, and the efforts to improve data quality by modifying the standard procedures. Additionally, we highlight recent advancements in ribosome profiling that enable the transition from bulk to low-input and single-cell applications. Single-cell ribosome profiling has emerged as a crucial tool for exploring translation heterogeneity within specific cell populations. However, the challenges of capturing mRNAs efficiently and the sparse nature of footprint reads in single-cell ribosome profiling present ongoing obstacles. The need to refine ribosome profiling techniques remains, especially when used at the single-cell level.
    Keywords:  Dual-ligation; Ribo-seq quality; Ribosome profiling; Template-switch
    DOI:  https://doi.org/10.1007/s44307-023-00006-4
  4. Signal Transduct Target Ther. 2025 Jan 27. 10(1): 43
    The cryptic lncRNA-encoded microprotein TPM3P9 drives oncogenic RNA splicing and tumorigenesis.
    Kun Meng, Yuying Li, Xiaoyi Yuan, Hui-Min Shen, Li-Ling Hu, Danya Liu, Fujin Shi, Dandan Zheng, Xinyu Shi, Nengqiao Wen, Yun Cao, Yun-Long Pan, Qing-Yu He, Chris Zhiyi Zhang.
      Emerging evidence demonstrates that cryptic translation from RNAs previously annotated as noncoding might generate microproteins with oncogenic functions. However, the importance and underlying mechanisms of these microproteins in alternative splicing-driven tumor progression have rarely been studied. Here, we show that the novel protein TPM3P9, encoded by the lncRNA tropomyosin 3 pseudogene 9, exhibits oncogenic activity in clear cell renal cell carcinoma (ccRCC) by enhancing oncogenic RNA splicing. Overexpression of TPM3P9 promotes cell proliferation and tumor growth. Mechanistically, TPM3P9 binds to the RRM1 domain of the splicing factor RBM4 to inhibit RBM4-mediated exon skipping in the transcription factor TCF7L2. This results in increased expression of the oncogenic splice variant TCF7L2-L, which activates NF-κB signaling via its interaction with SAM68 to transcriptionally induce RELB expression. From a clinical perspective, TPM3P9 expression is upregulated in cancer tissues and is significantly correlated with the expression of TCF7L2-L and RELB. High TPM3P9 expression or low RBM4 expression is associated with poor survival in patients with ccRCC. Collectively, our findings functionally and clinically characterize the "noncoding RNA"-derived microprotein TPM3P9 and thus identify potential prognostic and therapeutic factors in renal cancer.
    DOI:  https://doi.org/10.1038/s41392-025-02128-8
  5. Commun Biol. 2025 Jan 28. 8(1): 140
    Integrative multi-omics analysis reveals the translational landscape of the plant-parasitic nematode Meloidogyne incognita.
    Zhaolu Zhu, Dexin Bo, Chuanshuai Xie, Dadong Dai, Donghai Peng, Ming Sun, Jinshui Zheng.
      Root-knot nematodes (RKNs) of the genus Meloidogyne pose the most significant threats to global food security due to their destructive nature as plant-parasitic nematodes. Although significant attention has been devoted to investigating the gene transcription profiling of RKNs, our understanding of the translational landscape of RKNs remains limited. In this study, we elucidated the translational landscape of Meloidogyne incognita through the integration of translatome, transcriptome and quantitative proteome analyses. Our findings revealed numerous previously unannotated translation events and refined the genome annotation. By investigating the genome-wide translational dynamics of M. incognita during parasitism, we revealed that the genes of M. incognita undergo parasitic stage-specific regulation at the translational level. Interestingly, we identified 470 micropeptides (containing fewer than 100 amino acids) with the potential to function as effectors. Additionally, we observed that the effector-coding genes in M. incognita exhibit higher translation efficiency (TE). Further analysis suggests that M. incognita has the potential to regulate the TE of effector-coding genes without simultaneous alterations in their transcript abundance, facilitating effector synthesis. Collectively, our study provides comprehensive datasets and explores the genome-wide translational landscape of M. incognita, shedding light on the contributions of translational regulation during parasitism.
    DOI:  https://doi.org/10.1038/s42003-025-07533-x
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