bims-micpro Biomed News
on Discovery and characterization of microproteins
Issue of 2021–09–19
seven papers selected by
Thomas Farid Martínez, University of California, Irvine
  1. Discovery of a small protein-encoding cis-regulatory overlapping gene of the tumor suppressor gene Scribble in humans.
  2. Bacterial small membrane proteins: the Swiss army knife of regulators at the lipid bilayer.
  3. Mitochondrial-derived peptides and exercise.
  4. Pri smORF Peptides Are Wide Mediators of Ecdysone Signaling, Contributing to Shape Spatiotemporal Responses.
  5. A peptide CORO1C-47aa encoded by the circular non-coding RNA circ-0000437 functions as a negative regulator in endometrium tumor angiogenesis.
  6. A putative long noncoding RNA-encoded micropeptide maintains cellular homeostasis in pancreatic β cells.
  7. Mitochondrial-encoded MOTS-c prevents pancreatic islet destruction in autoimmune diabetes.
  1. Commun Biol. 2021 Sep 17. 4(1): 1098
    Discovery of a small protein-encoding cis-regulatory overlapping gene of the tumor suppressor gene Scribble in humans.
    Yuhta Nomura, Naoshi Dohmae.
      Intensive gene annotation has revealed many functional and regulatory elements in the human genome. Although eukaryotic protein-coding genes are generally transcribed into monocistronic mRNAs, recent studies have discovered additional short open reading frames (sORFs) in mRNAs. Here, we performed proteogenomic data mining for hidden proteins categorized into sORF-encoded polypeptides (SEPs) in human cancers. We identified a new SEP-encoding overlapping sORF (oORF) on the cell polarity determinant Scribble (SCRIB) that is considered a proto-oncogene with tumor suppressor function in Hippo-YAP/TAZ, MAPK/ERK, and PI3K/Akt/mTOR signaling. Reanalysis of clinical human proteomic data revealed translational dysregulation of both SCRIB and its oORF, oSCRIB, during carcinogenesis. Biochemical analyses suggested that the translatable oSCRIB constitutively limits the capacity of eukaryotic ribosomes to translate the downstream SCRIB. These findings provide a new example of cis-regulatory oORFs that function as a ribosomal roadblock and potentially serve as a fail-safe mechanism to normal cells for non-excessive downstream gene expression, which is hijacked in cancer.
    DOI:  https://doi.org/10.1038/s42003-021-02619-8
  2. J Bacteriol. 2021 Sep 13. JB0034421
    Bacterial small membrane proteins: the Swiss army knife of regulators at the lipid bilayer.
    Srujana S Yadavalli, Jing Yuan.
      Small membrane proteins represent a subset of recently discovered small proteins (≤100 amino acids), which are a ubiquitous class of emerging regulators underlying bacterial adaptation to environmental stressors. Until relatively recently, small open reading frames encoding these proteins were not designated as genes in genome annotations. Therefore, our understanding of small protein biology was primarily limited to a few candidates associated with previously characterized larger partner proteins. Following the first systematic analyses of small proteins in E. coli over a decade ago, numerous small proteins have been uncovered across different bacteria. An estimated one-third of these newly discovered proteins are localized to the cell membrane, where they may interact with distinct groups of membrane proteins such as signal receptors, transporters, and enzymes, and affect their activities. Recently, there has been considerable progress in functionally characterizing small membrane protein regulators aided by innovative tools adapted specifically to study small proteins. Our review covers prototypical proteins that modulate a broad range of cellular processes such as transport, signal transduction, stress response, respiration, cell division, sporulation as well as membrane stability. Thus, small membrane proteins represent a versatile group of regulators of physiology not just at the membrane but the whole cell. Additionally, small membrane proteins have the potential for clinical applications, where some of the proteins may act as antibacterial agents themselves, while others serve as alternative drug targets for the development of novel antimicrobials.
    DOI:  https://doi.org/10.1128/JB.00344-21
  3. Biochim Biophys Acta Gen Subj. 2021 Sep 11. pii: S0304-4165(21)00170-7. [Epub ahead of print] 130011
    Mitochondrial-derived peptides and exercise.
    Jonathan S T Woodhead, Troy L Merry.
      Acute exercise, and in particular aerobic exercise, increases skeletal muscle energy demand causing mitochondrial stress, and mitochondrial-related adaptations which are a hallmark of exercise training. Given that mitochondria are central players in the exercise response, it is imperative that they have networks that can communicate their status both intra- and inter-cellularly. Peptides encoded by short open-reading frames within mitochondrial DNA, mitochondrial-derived peptides (MDPs), have been suggested to form a newly recognised branch of this retrograde signalling cascade that contribute to coordinating the adaptive response to regular exercise. Here we summarise the recent evidence that acute high intensity exercise in humans can increase concentrations of the MDPs humanin and MOTS-c in skeletal muscle and plasma, and speculate on the mechanisms controlling MDP responses to exercise stress. Evidence that exercise training results in chronic changes in MDP expression within tissues and the circulation is conflicting and may depend on the mode, duration, intensity of training plan and participant characteristics. Further research is required to define the effect of these variables on MDPs and to determine whether MDPs other than MOTS-c have exercise mimetic properties. MOTS-c treatment of young and aged mice improves exercise capacity/performance and leads to adaptions that are similar to that of being physically active (weight loss, increased antioxidant capacity and improved insulin sensitivity), however, studies utilising a MOTS-c inactivating genetic variant or combination of exercise + MOTS-c treatment in mice suggest that there are distinct and overlapping pathways through which exercise and MOTS-c evoke metabolic benefits. Overall, MOTS-c, and potentially other MDPs, may be exercise-sensitive myokines and further work is required to define inter- and intra-tissue targets in an exercise context.
    Keywords:  Cellular signalling; Hormesis; Mitochondria; Muscle; Physical activity; ROS
    DOI:  https://doi.org/10.1016/j.bbagen.2021.130011
  4. Front Genet. 2021 ;12 714152
    Pri smORF Peptides Are Wide Mediators of Ecdysone Signaling, Contributing to Shape Spatiotemporal Responses.
    Azza Dib, Jennifer Zanet, Alexandra Mancheno-Ferris, Maylis Gallois, Damien Markus, Philippe Valenti, Simon Marques-Prieto, Serge Plaza, Yuji Kageyama, Hélène Chanut-Delalande, François Payre.
      There is growing evidence that peptides encoded by small open-reading frames (sORF or smORF) can fulfill various cellular functions and define a novel class regulatory molecules. To which extend transcripts encoding only smORF peptides compare with canonical protein-coding genes, yet remain poorly understood. In particular, little is known on whether and how smORF-encoding RNAs might need tightly regulated expression within a given tissue, at a given time during development. We addressed these questions through the analysis of Drosophila polished rice (pri, a.k.a. tarsal less or mille pattes), which encodes four smORF peptides (11-32 amino acids in length) required at several stages of development. Previous work has shown that the expression of pri during epidermal development is regulated in the response to ecdysone, the major steroid hormone in insects. Here, we show that pri transcription is strongly upregulated by ecdysone across a large panel of cell types, suggesting that pri is a core component of ecdysone response. Although pri is produced as an intron-less short transcript (1.5 kb), genetic assays reveal that the developmental functions of pri require an unexpectedly large array of enhancers (spanning over 50 kb), driving a variety of spatiotemporal patterns of pri expression across developing tissues. Furthermore, we found that separate pri enhancers are directly activated by the ecdysone nuclear receptor (EcR) and display distinct regulatory modes between developmental tissues and/or stages. Alike major developmental genes, the expression of pri in a given tissue often involves several enhancers driving apparently redundant (or shadow) expression, while individual pri enhancers can harbor pleiotropic functions across tissues. Taken together, these data reveal the broad role of Pri smORF peptides in ecdysone signaling and show that the cis-regulatory architecture of the pri gene contributes to shape distinct spatial and temporal patterns of ecdysone response throughout development.
    Keywords:  ecdysone; mille pattes; polished rice; smORF peptides; steroids; tarsal less
    DOI:  https://doi.org/10.3389/fgene.2021.714152
  5. J Biol Chem. 2021 Sep 14. pii: S0021-9258(21)00984-4. [Epub ahead of print] 101182
    A peptide CORO1C-47aa encoded by the circular non-coding RNA circ-0000437 functions as a negative regulator in endometrium tumor angiogenesis.
    Fang Li, Yuhan Cai, Sihan Deng, Lin Yang, Na Liu, Xiaohan Chang, Lankai Jing, Yifeng Zhou, Hua Li.
      Circular RNAs (circRNA) are a novel class of widespread non-coding RNAs (ncRNAs) that regulate gene expression in mammals. Recent studies demonstrate that functional peptides can be encoded by short open reading frames (sORFs) in ncRNAs, including circRNAs. However, the role of circRNAs in various physiological and pathological states, such as cancer, are not well understood. In this study, through deep RNA sequencing on human endometrial cancer (EC) samples and their paired adjacent normal tissues, we uncovered that the circRNA hsa-circ-0000437 is significantly reduced in EC compared to matched paracancerous tissue. The hsa-circ-0000437 contains a sORF encoding a functional peptide termed CORO1C-47aa. Overexpression of CORO1C-47aa is capable of inhibiting angiogenesis at the initiation stage by suppressing endothelial cell proliferation, migration, and differentiation through competition with transcription factor TACC3 to bind to ARNT and suppress VEGF. CORO1C-47aa directly bound to ARNT through the PAS-B domain and blocking the association between ARNT and TACC3 which led to reduced expression of VEGF ultimately lead to reduced angiogenesis. The anti-tumor effects of CORO1C-47aa on EC progression suggest that CORO1C-47aa has potential value in anti-carcinoma therapies and warrants further investigation.
    Keywords:  VEGF; angiogenesis; endometrial cancer; functional peptide; hsa-circ-0000437
    DOI:  https://doi.org/10.1016/j.jbc.2021.101182
  6. Mol Ther Nucleic Acids. 2021 Dec 03. 26 307-320
    A putative long noncoding RNA-encoded micropeptide maintains cellular homeostasis in pancreatic β cells.
    Mark Li, Fan Shao, Qingwen Qian, Wenjie Yu, Zeyuan Zhang, Biyi Chen, Dan Su, Yuwei Guo, An-Vi Phan, Long-Sheng Song, Samuel B Stephens, Julien Sebag, Yumi Imai, Ling Yang, Huojun Cao.
      Micropeptides (microproteins) encoded by transcripts previously annotated as long noncoding RNAs (lncRNAs) are emerging as important mediators of fundamental biological processes in health and disease. Here, we applied two computational tools to identify putative micropeptides encoded by lncRNAs that are expressed in the human pancreas. We experimentally verified one such micropeptide encoded by a β cell- and neural cell-enriched lncRNA TCL1 Upstream Neural Differentiation-Associated RNA (TUNAR, also known as TUNA, HI-LNC78, or LINC00617). We named this highly conserved 48-amino-acid micropeptide beta cell- and neural cell-regulin (BNLN). BNLN contains a single-pass transmembrane domain and localizes at the endoplasmic reticulum (ER) in pancreatic β cells. Overexpression of BNLN lowered ER calcium levels, maintained ER homeostasis, and elevated glucose-stimulated insulin secretion in pancreatic β cells. We further assessed the BNLN expression in islets from mice fed a high-fat diet and a regular diet and found that BNLN is suppressed by diet-induced obesity (DIO). Conversely, overexpression of BNLN enhanced insulin secretion in islets from lean and obese mice as well as from humans. Taken together, our study provides the first evidence that lncRNA-encoded micropeptides play a critical role in pancreatic β cell functions and provides a foundation for future comprehensive analyses of micropeptide function and pathophysiological impact on diabetes.
    Keywords:  computational biology; diabetes; endoplasmic reticulum; islets; lncRNA; micropeptides; sORF
    DOI:  https://doi.org/10.1016/j.omtn.2021.06.027
  7. Cell Rep. 2021 Sep 14. pii: S2211-1247(21)01173-6. [Epub ahead of print]36(11): 109724
    Mitochondrial-encoded MOTS-c prevents pancreatic islet destruction in autoimmune diabetes.
    Byung Soo Kong, Se Hee Min, Changhan Lee, Young Min Cho.
      
    DOI:  https://doi.org/10.1016/j.celrep.2021.109724
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