TUNAR lncRNA Encodes a Microprotein that Regulates Neural Differentiation and Neurite Formation by Modulating Calcium Dynamics
Long noncoding RNAs (lncRNAs) are regulatory molecules which have been traditionally considered as “non-coding”. Strikingly, recent evidence has demonstrated that many non-coding regions, including lncRNAs, do in fact contain small-open reading frames that code for small proteins that have been call...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-12-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2021.747667/full |
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| author | Elena Senís Miriam Esgleas Sonia Najas Verónica Jiménez-Sábado Camilla Bertani Marta Giménez-Alejandre Alba Escriche Jorge Ruiz-Orera Marta Hergueta-Redondo Mireia Jiménez Albert Giralt Paolo Nuciforo M. Mar Albà M. Mar Albà Héctor Peinado Daniel del Toro Leif Hove-Madsen Magdalena Götz María Abad |
| author_facet | Elena Senís Miriam Esgleas Sonia Najas Verónica Jiménez-Sábado Camilla Bertani Marta Giménez-Alejandre Alba Escriche Jorge Ruiz-Orera Marta Hergueta-Redondo Mireia Jiménez Albert Giralt Paolo Nuciforo M. Mar Albà M. Mar Albà Héctor Peinado Daniel del Toro Leif Hove-Madsen Magdalena Götz María Abad |
| author_sort | Elena Senís |
| collection | DOAJ |
| description | Long noncoding RNAs (lncRNAs) are regulatory molecules which have been traditionally considered as “non-coding”. Strikingly, recent evidence has demonstrated that many non-coding regions, including lncRNAs, do in fact contain small-open reading frames that code for small proteins that have been called microproteins. Only a few of them have been characterized so far, but they display key functions in a wide variety of cellular processes. Here, we show that TUNAR lncRNA encodes an evolutionarily conserved microprotein expressed in the nervous system that we have named pTUNAR. pTUNAR deficiency in mouse embryonic stem cells improves their differentiation potential towards neural lineage both in vitro and in vivo. Conversely, pTUNAR overexpression impairs neuronal differentiation by reduced neurite formation in different model systems. At the subcellular level, pTUNAR is a transmembrane protein that localizes in the endoplasmic reticulum and interacts with the calcium transporter SERCA2. pTUNAR overexpression reduces cytoplasmatic calcium, consistent with a possible role of pTUNAR as an activator of SERCA2. Altogether, our results suggest that our newly discovered microprotein has an important role in neural differentiation and neurite formation through the regulation of intracellular calcium. From a more general point of view, our results provide a proof of concept of the role of lncRNAs-encoded microproteins in neural differentiation. |
| first_indexed | 2024-04-11T20:48:59Z |
| format | Article |
| id | doaj.art-3dac13a368e84670974c18ed67fa60c7 |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-04-11T20:48:59Z |
| publishDate | 2021-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-3dac13a368e84670974c18ed67fa60c72022-12-22T04:03:55ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-12-01910.3389/fcell.2021.747667747667TUNAR lncRNA Encodes a Microprotein that Regulates Neural Differentiation and Neurite Formation by Modulating Calcium DynamicsElena Senís0Miriam Esgleas1Sonia Najas2Verónica Jiménez-Sábado3Camilla Bertani4Marta Giménez-Alejandre5Alba Escriche6Jorge Ruiz-Orera7Marta Hergueta-Redondo8Mireia Jiménez9Albert Giralt10Paolo Nuciforo11M. Mar Albà12M. Mar Albà13Héctor Peinado14Daniel del Toro15Leif Hove-Madsen16Magdalena Götz17María Abad18Cellular Plasticity and Cancer Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, SpainPhysiological Genomics, Biomedical Center (BMC), Helmholtz Center Munich, Institute of Stem Cell Research, Großhaderner Str, SyNergy Excellence Cluster, Ludwig-Maximilians-Universitaet (LMU), Munich, GermanyPhysiological Genomics, Biomedical Center (BMC), Helmholtz Center Munich, Institute of Stem Cell Research, Großhaderner Str, SyNergy Excellence Cluster, Ludwig-Maximilians-Universitaet (LMU), Munich, GermanyInstituto de Investigación Biomédica Barcelona (IIBB-CSIC), Instituto de Investigación Biomédica Sant Pau (IIB-Sant Pau) and CIBERCV, Barcelona, SpainCellular Plasticity and Cancer Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, SpainCellular Plasticity and Cancer Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, SpainCellular Plasticity and Cancer Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, SpainCardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, GermanyMicroenvironment and Metastasis Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), Madrid, SpainCellular Plasticity and Cancer Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, SpainDepartment of Biological Sciences, Institute of Neurosciences, IDIBAPS, CIBERNED, University of Barcelona, Barcelona, SpainMolecular Oncology Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, SpainEvolutionary Genomics Group, Research Programme on Biomedical Informatics, Hospital del Mar Medical Research Institute (IMIM) and Universitat Pompeu Fabra (UPF), Barcelona, SpainCatalan Institution for Research and Advanced Studies (ICREA), Barcelona, SpainMicroenvironment and Metastasis Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), Madrid, SpainDepartment of Biological Sciences, Institute of Neurosciences, IDIBAPS, CIBERNED, University of Barcelona, Barcelona, SpainInstituto de Investigación Biomédica Barcelona (IIBB-CSIC), Instituto de Investigación Biomédica Sant Pau (IIB-Sant Pau) and CIBERCV, Barcelona, SpainPhysiological Genomics, Biomedical Center (BMC), Helmholtz Center Munich, Institute of Stem Cell Research, Großhaderner Str, SyNergy Excellence Cluster, Ludwig-Maximilians-Universitaet (LMU), Munich, GermanyCellular Plasticity and Cancer Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, SpainLong noncoding RNAs (lncRNAs) are regulatory molecules which have been traditionally considered as “non-coding”. Strikingly, recent evidence has demonstrated that many non-coding regions, including lncRNAs, do in fact contain small-open reading frames that code for small proteins that have been called microproteins. Only a few of them have been characterized so far, but they display key functions in a wide variety of cellular processes. Here, we show that TUNAR lncRNA encodes an evolutionarily conserved microprotein expressed in the nervous system that we have named pTUNAR. pTUNAR deficiency in mouse embryonic stem cells improves their differentiation potential towards neural lineage both in vitro and in vivo. Conversely, pTUNAR overexpression impairs neuronal differentiation by reduced neurite formation in different model systems. At the subcellular level, pTUNAR is a transmembrane protein that localizes in the endoplasmic reticulum and interacts with the calcium transporter SERCA2. pTUNAR overexpression reduces cytoplasmatic calcium, consistent with a possible role of pTUNAR as an activator of SERCA2. Altogether, our results suggest that our newly discovered microprotein has an important role in neural differentiation and neurite formation through the regulation of intracellular calcium. From a more general point of view, our results provide a proof of concept of the role of lncRNAs-encoded microproteins in neural differentiation.https://www.frontiersin.org/articles/10.3389/fcell.2021.747667/fullmicroproteinsmicropeptidessORF encoded peptidesTUNARneural differentiationneurite formation |
| spellingShingle | Elena Senís Miriam Esgleas Sonia Najas Verónica Jiménez-Sábado Camilla Bertani Marta Giménez-Alejandre Alba Escriche Jorge Ruiz-Orera Marta Hergueta-Redondo Mireia Jiménez Albert Giralt Paolo Nuciforo M. Mar Albà M. Mar Albà Héctor Peinado Daniel del Toro Leif Hove-Madsen Magdalena Götz María Abad TUNAR lncRNA Encodes a Microprotein that Regulates Neural Differentiation and Neurite Formation by Modulating Calcium Dynamics Frontiers in Cell and Developmental Biology microproteins micropeptides sORF encoded peptides TUNAR neural differentiation neurite formation |
| title | TUNAR lncRNA Encodes a Microprotein that Regulates Neural Differentiation and Neurite Formation by Modulating Calcium Dynamics |
| title_full | TUNAR lncRNA Encodes a Microprotein that Regulates Neural Differentiation and Neurite Formation by Modulating Calcium Dynamics |
| title_fullStr | TUNAR lncRNA Encodes a Microprotein that Regulates Neural Differentiation and Neurite Formation by Modulating Calcium Dynamics |
| title_full_unstemmed | TUNAR lncRNA Encodes a Microprotein that Regulates Neural Differentiation and Neurite Formation by Modulating Calcium Dynamics |
| title_short | TUNAR lncRNA Encodes a Microprotein that Regulates Neural Differentiation and Neurite Formation by Modulating Calcium Dynamics |
| title_sort | tunar lncrna encodes a microprotein that regulates neural differentiation and neurite formation by modulating calcium dynamics |
| topic | microproteins micropeptides sORF encoded peptides TUNAR neural differentiation neurite formation |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2021.747667/full |
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