TUNAR lncRNA encodes a microprotein that regulates neural differentiation and neurite formation by modulating calcium dynamics

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• dc.contributor.author Senís, Elena
• dc.contributor.author Esgleas, Miriam
• dc.contributor.author Najas Sales, Sònia, 1985-
• dc.contributor.author Jiménez-Sábado, Verónica
• dc.contributor.author Bertani, Camilla
• dc.contributor.author Giménez-Alejandre, Marta
• dc.contributor.author Escriche, Alba
• dc.contributor.author Ruiz Orera, Jorge, 1988-
• dc.contributor.author Hergueta-Redondo, Marta
• dc.contributor.author Jiménez, Mireia
• dc.contributor.author Giralt, Albert
• dc.contributor.author Nuciforo, Paolo G.
• dc.contributor.author Albà Soler, Mar
• dc.contributor.author Peinado, Héctor
• dc.contributor.author Toro, Daniel
• dc.contributor.author Hove-Madsen, Leif
• dc.contributor.author Götz, Magdalena
• dc.contributor.author Abad, María
• dc.date.accessioned 2022-09-19T06:19:06Z
• dc.date.available 2022-09-19T06:19:06Z
• dc.date.issued 2021
• dc.description.abstract 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.
• dc.description.sponsorship Work in the Abad lab is supported by VHIO, Fero Foundation, La Caixa Foundation (HR18-00256), Asociación Española Contra el Cancer (AECC), Cellex Foundation, Mutua Madrileña Foundation and by grants from the Spanish Ministry of Science and Innovation (SAF2015-69413-R; RTI2018-102046-B-I00). M.A. was recipient of a Ramon y Cajal contract from the Spanish Ministry of Science and Innovation (RYC-2013-14747). E.S. was recipient of a AECC Postdoctoral Fellowship. L.H-M. also acknowledges funding from grants SAF2017-88019-C3-1R y PID2020-116927RB-C21 from the Spanish Government. MG is supported by the advanced ERC grant NeuroCentro and the German Research Foundation (SFB870; SPP2202; SPP2306; SYNERGY; TRR274). DT is supported by the Ramón y Cajal program (RYC-2017-23486/RTI2018-095580-A-I00). MMA acknowledges funding from the Spanish Ministry of Science and Innovation PGC2018-094091-B-I00 co-funded by FEDER.
• dc.format.mimetype application/pdf
• dc.identifier.citation Senís E, Esgleas M, Najas S, Jiménez-Sábado V, Bertani C, Giménez-Alejandre M, Escriche A, Ruiz-Orera J, Hergueta-Redondo M, Jiménez M, Giralt A, Nuciforo P, Albà MM, Peinado H, Del Toro D, Hove-Madsen L, Götz M, Abad M. TUNAR lncRNA encodes a microprotein that regulates neural differentiation and neurite formation by modulating calcium dynamics. Front Cell Dev Biol. 2021 Dec 31;9:747667. DOI: 10.3389/fcell.2021.747667
• dc.identifier.doi http://dx.doi.org/10.3389/fcell.2021.747667
• dc.identifier.issn 2296-634X
• dc.identifier.uri http://hdl.handle.net/10230/54101
• dc.language.iso eng
• dc.publisher Frontiers
• dc.relation.ispartof Front Cell Dev Biol. 2021 Dec 31;9:747667
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2015-69413-R
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-102046-B-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/RYC-2013-14747
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/SAF2017-88019-C3-1R
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-116927RB-C21
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PGC2018-094091-B-I00
• dc.rights © 2021 Senís, Esgleas, Najas, Jiménez-Sábado, Bertani, Giménez-Alejandre, Escriche, Ruiz-Orera, Hergueta-Redondo, Jiménez, Giralt, Nuciforo, Albà, Peinado, Toro, Hove-Madsen, Götz and Abad. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword TUNAR
• dc.subject.keyword Calcium
• dc.subject.keyword Long non-coding RNAs
• dc.subject.keyword Micropeptides
• dc.subject.keyword Microproteins
• dc.subject.keyword Neural differentiation
• dc.subject.keyword Neurite formation
• dc.subject.keyword sORF encoded peptides
• dc.title TUNAR lncRNA encodes a microprotein that regulates neural differentiation and neurite formation by modulating calcium dynamics
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion