bims-micpro Biomed News
on Discovery and characterization of microproteins
Issue of 2022‒10‒02
five papers selected by
Thomas Farid Martínez
University of California, Irvine

  1. Nat Neurosci. 2022 Sep 28.
      The precise regulation of gene expression is fundamental to neurodevelopment, plasticity and cognitive function. Although several studies have profiled transcription in the developing human brain, there is a gap in understanding of accompanying translational regulation. In this study, we performed ribosome profiling on 73 human prenatal and adult cortex samples. We characterized the translational regulation of annotated open reading frames (ORFs) and identified thousands of previously unknown translation events, including small ORFs that give rise to human-specific and/or brain-specific microproteins, many of which we independently verified using proteomics. Ribosome profiling in stem-cell-derived human neuronal cultures corroborated these findings and revealed that several neuronal activity-induced non-coding RNAs encode previously undescribed microproteins. Physicochemical analysis of brain microproteins identified a class of proteins that contain arginine-glycine-glycine (RGG) repeats and, thus, may be regulators of RNA metabolism. This resource expands the known translational landscape of the human brain and illuminates previously unknown brain-specific protein products.
  2. Cell Calcium. 2022 Sep 22. pii: S0143-4160(22)00128-2. [Epub ahead of print]107 102655
      Micropeptides regulate cellular calcium handling by modulating the function of the calcium transporter SERCA. In a recent Nature Communications paper [4] authors Schiemann et al. describe regulation of an invertebrate SERCA-active micropeptide, sarcolamban, by an endopeptidase called neprilysin 4 (NEP4). NEP4 activity limits sarcolamban expression by cleavage of luminal residues near the micropeptide's c-terminus. This cleavage event liberates sarcolamban from the membrane, reduces its oligomerization, and prevents it from inhibiting SERCA. The study reveals a novel mechanism for "regulation of the regulator" that may be a general feature of micropeptide/SERCA physiology.
    Keywords:  Endopeptidase; Membrane transport; Micropeptides; SERCA; Sarcolamban
  3. Elife. 2022 Sep 30. pii: e78772. [Epub ahead of print]11
      De novo gene origination, where a previously non-genic genomic sequence becomes genic through evolution, has been increasingly recognized as an important source of evolutionary novelty across diverse taxa. Many de novo genes have been proposed to be protein-coding, and in several cases have been experimentally shown to yield protein products. However, the systematic study of de novo proteins has been hampered by doubts regarding the translation of their transcripts without the experimental observation of protein products. Using a systematic, ORF-focused mass-spectrometry-first computational approach, we identify almost 1000 unannotated open reading frames with evidence of translation (utORFs) in the model organism Drosophila melanogaster, 371 of which have canonical start codons. To quantify the comparative genomic similarity of these utORFs across Drosophila and to infer phylostratigraphic age, we further develop a synteny-based protein similarity approach. Combining these results with reference datasets on tissue- and life-stage-specific transcription and conservation, we identify different properties amongst these utORFs. Contrary to expectations, the fastest-evolving utORFs are not the youngest evolutionarily. We observed more utORFs in the brain than in the testis. Most of the identified utORFs may be of de novo origin, even accounting for the possibility of false-negative similarity detection. Finally, sequence divergence after an inferred de novo origin event remains substantial, raising the possibility that de novo proteins turn over frequently. Our results suggest that there is substantial unappreciated diversity in de novo protein evolution: many more may exist than have been previously appreciated; there may be divergent evolutionary trajectories; and de novo proteins may be gained and lost frequently. All in all, there may not exist a single characteristic model of de novo protein evolution, but instead, there may be diverse evolutionary trajectories for de novo proteins.
    Keywords:  D. melanogaster; evolutionary biology; genetics; genomics
  4. Biochimie. 2022 Sep 26. pii: S0300-9084(22)00234-6. [Epub ahead of print]
      Mitoregulin (Mtln) is a recently identified 56 aminoacid long mitochondrial peptide conserved in vertebrates. Mtln is known to enhance function of respiratory complex I, which is likely mediated by modulation of lipid composition. To address an influence of Mtln gene on the metabolism we created knockout mice deficient in Mtln gene. In line with accumulation of triglycerides observed earlier on a model of Mtln knockout cell lines, we observed Mtln KO mice to develop obesity on a high fat diet. An increased weight gain could be attributed to enhanced fat accumulation according to the magnetic resonance live imaging. In addition, Mtln KO mice demonstrate elevated serum triglycerides and other oxidation substrates accompanied by an exhaustion of tricarboxylic acids cycle intermediates, suggesting suboptimal oxidation of respiration substrates by mitochondria lacking Mtln.
    Keywords:  Metabolism; Mitochondria; Oxidative phosphorylation; Short open reading frame; Small peptide
  5. J Cell Mol Med. 2022 Sep 25.
      MOTS-c, a mitochondrial-derived peptide (MDP), has been shown to have multiple biological activities such as antioxidation, anti-inflammation, and anti-apoptosis properties. In the present study, we aimed at evaluating the therapeutic effect of MOTS-c peptide in an animal model of heart failure. The heart failure mouse model was made by transverse aortic constriction (TAC) operations. The MOTS-c peptide was administrated subcutaneously by using an osmotic pump. At the end of the animal experiment, cardiac function was evaluated by echocardiography, and heart tissues were subjected to histological and molecular analysis. In vitro cultured H9C2 cells were used to test the effects of MOTS-c overexpression on cell death in response to H2 O2 stimulation. Our study showed that MOTS-c peptide attenuated TAC-induced cardiac dysfunction and remodelling. In addition, the MOTS-c peptide reduced the inflammatory response and upregulated the antioxidant capacity, coupled with the activation of the AMPK pathway in the heart of the TAC mouse model. In in vitro cultured cardiac cells, overexpression of MOTS-c was shown to activate the AMPK pathway and protect cell apoptosis in response to H2 O2 stimulation. Taken together, our study suggested that MOTS-c peptides may have therapeutic potential in treating HF.
    Keywords:  MOTS-c; heart failure; inflammation; oxidative stress; pressure overload