bims-micpro Biomed News
on Discovery and characterization of microproteins
Issue of 2022–11–13
five papers selected by
Thomas Farid Martínez, University of California, Irvine
  1. pTINCR microprotein promotes epithelial differentiation and suppresses tumor growth through CDC42 SUMOylation and activation.
  2. Pervasive translation of small open reading frames in plant long non-coding RNAs.
  3. Two neuronal peptides encoded from a single transcript regulate mitochondrial complex III in Drosophila.
  4. The mitochondrial micropeptide Stmp1 promotes retinal cell differentiation.
  5. Plant microProteins: Small but powerful modulators of plant development.
  1. Nat Commun. 2022 Nov 11. 13(1): 6840
    pTINCR microprotein promotes epithelial differentiation and suppresses tumor growth through CDC42 SUMOylation and activation.
    Olga Boix, Marion Martinez, Santiago Vidal, Marta Giménez-Alejandre, Lluís Palenzuela, Laura Lorenzo-Sanz, Laura Quevedo, Olivier Moscoso, Jorge Ruiz-Orera, Pilar Ximénez-Embún, Nikaoly Ciriaco, Paolo Nuciforo, Camille Stephan-Otto Attolini, M Mar Albà, Javier Muñoz, Tian V Tian, Ignacio Varela, Ana Vivancos, Santiago Ramón Y Cajal, Purificación Muñoz, Carmen Rivas, María Abad.
      The human transcriptome contains thousands of small open reading frames (sORFs) that encode microproteins whose functions remain largely unexplored. Here, we show that TINCR lncRNA encodes pTINCR, an evolutionary conserved ubiquitin-like protein (UBL) expressed in many epithelia and upregulated upon differentiation and under cellular stress. By gain- and loss-of-function studies, we demonstrate that pTINCR is a key inducer of epithelial differentiation in vitro and in vivo. Interestingly, low expression of TINCR associates with worse prognosis in several epithelial cancers, and pTINCR overexpression reduces malignancy in patient-derived xenografts. At the molecular level, pTINCR binds to SUMO through its SUMO interacting motif (SIM) and to CDC42, a Rho-GTPase critical for actin cytoskeleton remodeling and epithelial differentiation. Moreover, pTINCR increases CDC42 SUMOylation and promotes its activation, triggering a pro-differentiation cascade. Our findings suggest that the microproteome is a source of new regulators of cell identity relevant for cancer.
    DOI:  https://doi.org/10.1038/s41467-022-34529-6
  2. Front Plant Sci. 2022 ;13 975938
    Pervasive translation of small open reading frames in plant long non-coding RNAs.
    K Bharathan Sruthi, Athira Menon, Akash P, Eppurath Vasudevan Soniya.
      Long non-coding RNAs (lncRNAs) are primarily recognized as non-coding transcripts longer than 200 nucleotides with low coding potential and are present in both eukaryotes and prokaryotes. Recent findings reveal that lncRNAs can code for micropeptides in various species. Micropeptides are generated from small open reading frames (smORFs) and have been discovered frequently in short mRNAs and non-coding RNAs, such as lncRNAs, circular RNAs, and pri-miRNAs. The most accepted definition of a smORF is an ORF containing fewer than 100 codons, and ribosome profiling and mass spectrometry are the most prevalent experimental techniques used to identify them. Although the majority of micropeptides perform critical roles throughout plant developmental processes and stress conditions, only a handful of their functions have been verified to date. Even though more research is being directed toward identifying micropeptides, there is still a dearth of information regarding these peptides in plants. This review outlines the lncRNA-encoded peptides, the evolutionary roles of such peptides in plants, and the techniques used to identify them. It also describes the functions of the pri-miRNA and circRNA-encoded peptides that have been identified in plants.
    Keywords:  long non-coding RNA; miPEPs; micro peptides; non-coding RNAs; small ORF
    DOI:  https://doi.org/10.3389/fpls.2022.975938
  3. Elife. 2022 Nov 08. pii: e82709. [Epub ahead of print]11
    Two neuronal peptides encoded from a single transcript regulate mitochondrial complex III in Drosophila.
    Justin A Bosch, Berrak Ugur, Israel Pichardo-Casas, Jordan Rabasco, Felipe Escobedo, Zhongyuan Zuo, Ben Brown, Susan Celniker, David A Sinclair, Hugo J Bellen, Norbert Perrimon.
      Naturally produced peptides (<100 amino acids) are important regulators of physiology, development, and metabolism. Recent studies have predicted that thousands of peptides may be translated from transcripts containing small open reading frames (smORFs). Here, we describe two peptides in Drosophila encoded by conserved smORFs, Sloth1 and Sloth2. These peptides are translated from the same bicistronic transcript and share sequence similarities, suggesting that they encode paralogs. Yet, Sloth1 and Sloth2 are not functionally redundant, and loss of either peptide causes animal lethality, reduced neuronal function, impaired mitochondrial function, and neurodegeneration. We provide evidence that Sloth1/2 are highly expressed in neurons, imported to mitochondria, and regulate mitochondrial complex III assembly. These results suggest that phenotypic analysis of smORF genes in Drosophila can provide a wealth of information on the biological functions of this poorly characterized class of genes.
    Keywords:  D. melanogaster; genetics; genomics; neuroscience
    DOI:  https://doi.org/10.7554/eLife.82709
  4. Biochem Biophys Res Commun. 2022 Nov 03. pii: S0006-291X(22)01526-1. [Epub ahead of print]636(Pt 2): 79-86
    The mitochondrial micropeptide Stmp1 promotes retinal cell differentiation.
    Xintong Zheng, Yanan Guo, Rong Zhang, Haiqiao Chen, Shuting Liu, Suo Qiu, Mengqing Xiang.
      During mammalian retinal development, the differentiation of multipotent progenitors depends on the coordinated action of a variety of intrinsic factors including non-coding RNAs (ncRNAs). To date, many small open reading frames have been identified in ncRNAs to encode micropeptides that function in diverse biological processes; however, it remains unclear whether they have a role in retinal development. Here we report that the 47-amino acid (AA) mitochondrial micropeptide Stmp1 encoded by the lncRNA 1810058I24Rik is involved in retinal differentiation. As the major protein product of 1810058I24Rik, Stmp1 promotes the differentiation of bipolar, amacrine and Müller cells as 1810058I24Rik does when overexpressed in neonatal murine retinas. Moreover, we have identified the 15-AA N-terminus of Stmp1 as its mitochondrion-targeting sequence as well as 5 conserved AA residues that affect protein stability and/or retinal cell differentiation. Together, our data reveal several novel characteristics of Stmp1 and uncover a role for Stmp1 in retinal cell differentiation perhaps through regulating mitochondrial function.
    Keywords:  Differentiation; Micropeptide; Mitochondria; Retinal development; Stmp1
    DOI:  https://doi.org/10.1016/j.bbrc.2022.10.107
  5. iScience. 2022 Nov 18. 25(11): 105400
    Plant microProteins: Small but powerful modulators of plant development.
    Amit Kumar Kushwaha, Shubhi Dwivedi, Arpan Mukherjee, Maneesh Lingwan, Mansoor Ali Dar, Lavanya Bhagavatula, Sourav Datta.
      MicroProteins (miPs) are small and single-domain containing proteins of less than 20 kDa. This domain allows microProteins to interact with compatible domains of evolutionary-related proteins and fine-tuning the key physiological pathways in several organisms. Since the first report of a microProtein in mice, numerous microProteins have been identified in plants by computational approaches. However, only a few candidates have been functionally characterized, primarily in Arabidopsis. The recent success of synthetic microProteins in modulating physiological activities in crops makes these proteins interesting candidates for crop engineering. Here, we comprehensively summarise the synthesis, mode of action, and functional roles of microProteins in plants. We also discuss different approaches used to identify plant microProteins. Additionally, we discuss novel approaches to design synthetic microProteins that can be used to target proteins regulating plant growth and development. We finally highlight the prospects and challenges of utilizing microProteins in future crop improvement programs.
    Keywords:  Biomolecules; plant biology; plant development
    DOI:  https://doi.org/10.1016/j.isci.2022.105400
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