bims-micpro Biomed News
on Discovery and characterization of microproteins
Issue of 2020‒05‒17
four papers selected by
Thomas Martinez
Salk Institute for Biological Studies

  1. Exp Cell Res. 2020 May 05. pii: S0014-4827(20)30288-3. [Epub ahead of print] 112056
      Mitochondrial-derived peptides (MDPs) are a novel class of bioactive microproteins that modify cell metabolism. To date, eight MDPs have been characterized (e.g., humanin, MOTS-c, SHLPs1-6) and attenuate disease pathology, including Alzheimer's disease, prostate cancer, macular degeneration, cardiovascular disease, and diabetes. Human genetic variation in these MDPs is underexplored, but two polymorphisms in humanin and MOTS-c associate with cognitive decline and diabetes, respectively, suggesting a precise role for MDPs in disease-modification. There could be hundreds of additional MDPs that have yet to be discovered. Altogether, MDPs could explain unanswered biological and metabolic questions and are part of a growing field of novel microproteins encoded by small open reading frames. In this review, the current state of MDPs are summarized with an emphasis on biological and therapeutic implications.
    Keywords:  Microproteins; Mitochondrial-derived peptides; Small open reading frames
  2. Cell Death Dis. 2020 May 11. 11(5): 357
      In recent years, micropeptides have been increasingly identified as important regulators in various biological processes. However, whether micropeptides are functionally conserved remains largely unknown. Here, we uncovered a micropeptide with evolutionarily conserved roles in myogenesis. RNA-seq data analysis of proliferating mouse satellite cells (SCs) and differentiated myotubes identified a previously annotated lncRNA, MyolncR4 (1500011K16RIK), which is upregulated during muscle differentiation. Significantly, MyolncR4 is highly conserved across vertebrate species. Multiple lines of evidence demonstrate that MyolncR4 encodes a 56-aa micropeptide, which was named as LEMP (lncRNA encoded micropeptide). LEMP promotes muscle formation and regeneration in mouse. In zebrafish, MyolncR4 is enriched in developing somites and elimination of LEMP results in impaired muscle development, which could be efficiently rescued by expression of the mouse LEMP. Interestingly, LEMP is localized at both the plasma membrane and mitochondria, and associated with multiple mitochondrial proteins, suggestive of its involvement in mitochondrial functions. Together, our work uncovers a micropeptide that plays an evolutionarily conserved role in skeletal muscle differentiation, pinpointing the functional importance of this growing family of small peptides.
  3. Exp Cell Res. 2020 May 05. pii: S0014-4827(20)30289-5. [Epub ahead of print] 112057
      The discovery of functional yet non-annotated open reading frames (ORFs) throughout the genome of several species presents an unprecedented challenge in current genome annotation. These novel ORFs are shorter than annotated ones and many can be found on the same RNA, in opposition to current assumptions in annotation methodologies. Whilst the literature lacks consensus, these novel ORFs are commonly referred to as small ORFs (sORFs) or alternative ORFs (alt-ORFs). Unannotated ORFs represent an overlooked layer of complexity in the coding potential of genomes and are transforming our current vision of the nature of coding genes. In this review, we outline what constitutes a sORF or an alt-ORF and emphasize differences between both nomenclatures. We then describe complementary large-scale methods to accurately discover altORFs as well as yield functional insights on the novel proteins they encode. While serendipitous discoveries highlighted the functional importance of some novel ORFs, omics methods facilitate and improve their characterization to better understand physiological and pathological pathways. Functional annotation of sORFs, alt-ORFs and their corresponding microproteins will likely help fundamental and clinical research.
  4. Plants (Basel). 2020 May 11. pii: E608. [Epub ahead of print]9(5):
      Upstream open reading frames (uORFs) are present in the 5' leader sequences (or 5' untranslated regions) upstream of the protein-coding main ORFs (mORFs) in eukaryotic polycistronic mRNA. It is well known that a uORF negatively affects translation of the mORF. Emerging ribosome profiling approaches have revealed that uORFs themselves, as well as downstream mORFs, can be translated. However, it has also been revealed that plants can fine-tune gene expression by modulating uORF-mediated regulation in some situations. This article reviews several proposed mechanisms that enable genes to escape from uORF-mediated negative regulation and gives insight into the application of uORF-mediated regulation for precisely controlling gene expression.
    Keywords:  NMD; ribosome; translation; uORF