Macrophage inflammation resolution requires CPEB4-directed offsetting of mRNA degradation

Chronic inflammation is a major cause of disease. Inflammation resolution is in part directed by the differential stability of mRNAs encoding pro-inflammatory and anti-inflammatory factors. In particular, tristetraprolin (TTP)-directed mRNA deadenylation destabilizes AU-rich element (ARE)-containing...

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Detalles Bibliográficos
Autores: Suñer, Clara, Sibilio, Annarita, Martín, Judit, Castellazzi, Chiara Lara, Reina García, Óscar, 1976-, Dotu, Ivan, Caballé, Adrià, Rivas, Elisa, Calderone, Vittorio, Díez Antón, Juana, 1962-, Nebreda, Ángel R., Méndez de la Iglesia, Raúl
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10230/53542
Acceso en línea:http://hdl.handle.net/10230/53542
http://dx.doi.org/10.7554/eLife.75873
Access Level:acceso abierto
Palabra clave:CPEB
MAPK
RNA Binding Protein
TTP
Cell biology
mRNA stability
Mouse
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network_name_str España
repository_id_str
spelling Macrophage inflammation resolution requires CPEB4-directed offsetting of mRNA degradationSuñer, ClaraSibilio, AnnaritaMartín, JuditCastellazzi, Chiara LaraReina García, Óscar, 1976-Dotu, IvanCaballé, AdriàRivas, ElisaCalderone, VittorioDíez Antón, Juana, 1962-Nebreda, Ángel R.Méndez de la Iglesia, RaúlCPEBMAPKRNA Binding ProteinTTPCell biologymRNA stabilityMouseChronic inflammation is a major cause of disease. Inflammation resolution is in part directed by the differential stability of mRNAs encoding pro-inflammatory and anti-inflammatory factors. In particular, tristetraprolin (TTP)-directed mRNA deadenylation destabilizes AU-rich element (ARE)-containing mRNAs. However, this mechanism alone cannot explain the variety of mRNA expression kinetics that are required to uncouple degradation of pro-inflammatory mRNAs from the sustained expression of anti-inflammatory mRNAs. Here, we show that the RNA-binding protein CPEB4 acts in an opposing manner to TTP in macrophages: it helps to stabilize anti-inflammatory transcripts harboring cytoplasmic polyadenylation elements (CPEs) and AREs in their 3'-UTRs, and it is required for the resolution of the lipopolysaccharide (LPS)-triggered inflammatory response. Coordination of CPEB4 and TTP activities is sequentially regulated through MAPK signaling. Accordingly, CPEB4 depletion in macrophages impairs inflammation resolution in an LPS-induced sepsis model. We propose that the counterbalancing actions of CPEB4 and TTP, as well as the distribution of CPEs and AREs in their target mRNAs, define transcript-specific decay patterns required for inflammation resolution. Thus, these two opposing mechanisms provide a fine-tuning control of inflammatory transcript destabilization while maintaining the expression of the negative feedback loops required for efficient inflammation resolution; disruption of this balance can lead to disease.We thank the Biostatistics/Bioinformatics, Histopathology, Mouse Mutant, and Functional Genomics facilities at IRB Barcelona. The Flow Cytometry Facility of the UB/PCB and the CRG Genomic Unit are also acknowledged. We thank Dr. Mercedes Fernández and members of the labs of Dr. Angel Nebreda and Dr. Raul Méndez for useful discussion. This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (MINECO, BFU2017-83561-P), the Fundación BBVA, the Fundación Bancaria 'la Caixa,' the Fundació La Marató TV3, and the Scientific Foundation of the Spanish Association Against Cancer (AECC). CS is the recipient of an FPI-Severo Ochoa fellowship from MINECO. IRB Barcelona is the recipient of a Severo Ochoa Award of Excellence from MINECO (Government of Spain) and was supported by the CERCA Programme (Catalan Government).eLife202220222022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/53542http://dx.doi.org/10.7554/eLife.75873reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésElife. 2022 Apr 20;11:e75873info:eu-repo/grantAgreement/ES/2PE/BFU2017-83561-P© 2022, Suñer et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:10230/535422026-05-29T05:05:01Z
dc.title.none.fl_str_mv Macrophage inflammation resolution requires CPEB4-directed offsetting of mRNA degradation
title Macrophage inflammation resolution requires CPEB4-directed offsetting of mRNA degradation
spellingShingle Macrophage inflammation resolution requires CPEB4-directed offsetting of mRNA degradation
Suñer, Clara
CPEB
MAPK
RNA Binding Protein
TTP
Cell biology
mRNA stability
Mouse
title_short Macrophage inflammation resolution requires CPEB4-directed offsetting of mRNA degradation
title_full Macrophage inflammation resolution requires CPEB4-directed offsetting of mRNA degradation
title_fullStr Macrophage inflammation resolution requires CPEB4-directed offsetting of mRNA degradation
title_full_unstemmed Macrophage inflammation resolution requires CPEB4-directed offsetting of mRNA degradation
title_sort Macrophage inflammation resolution requires CPEB4-directed offsetting of mRNA degradation
dc.creator.none.fl_str_mv Suñer, Clara
Sibilio, Annarita
Martín, Judit
Castellazzi, Chiara Lara
Reina García, Óscar, 1976-
Dotu, Ivan
Caballé, Adrià
Rivas, Elisa
Calderone, Vittorio
Díez Antón, Juana, 1962-
Nebreda, Ángel R.
Méndez de la Iglesia, Raúl
author Suñer, Clara
author_facet Suñer, Clara
Sibilio, Annarita
Martín, Judit
Castellazzi, Chiara Lara
Reina García, Óscar, 1976-
Dotu, Ivan
Caballé, Adrià
Rivas, Elisa
Calderone, Vittorio
Díez Antón, Juana, 1962-
Nebreda, Ángel R.
Méndez de la Iglesia, Raúl
author_role author
author2 Sibilio, Annarita
Martín, Judit
Castellazzi, Chiara Lara
Reina García, Óscar, 1976-
Dotu, Ivan
Caballé, Adrià
Rivas, Elisa
Calderone, Vittorio
Díez Antón, Juana, 1962-
Nebreda, Ángel R.
Méndez de la Iglesia, Raúl
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv CPEB
MAPK
RNA Binding Protein
TTP
Cell biology
mRNA stability
Mouse
topic CPEB
MAPK
RNA Binding Protein
TTP
Cell biology
mRNA stability
Mouse
description Chronic inflammation is a major cause of disease. Inflammation resolution is in part directed by the differential stability of mRNAs encoding pro-inflammatory and anti-inflammatory factors. In particular, tristetraprolin (TTP)-directed mRNA deadenylation destabilizes AU-rich element (ARE)-containing mRNAs. However, this mechanism alone cannot explain the variety of mRNA expression kinetics that are required to uncouple degradation of pro-inflammatory mRNAs from the sustained expression of anti-inflammatory mRNAs. Here, we show that the RNA-binding protein CPEB4 acts in an opposing manner to TTP in macrophages: it helps to stabilize anti-inflammatory transcripts harboring cytoplasmic polyadenylation elements (CPEs) and AREs in their 3'-UTRs, and it is required for the resolution of the lipopolysaccharide (LPS)-triggered inflammatory response. Coordination of CPEB4 and TTP activities is sequentially regulated through MAPK signaling. Accordingly, CPEB4 depletion in macrophages impairs inflammation resolution in an LPS-induced sepsis model. We propose that the counterbalancing actions of CPEB4 and TTP, as well as the distribution of CPEs and AREs in their target mRNAs, define transcript-specific decay patterns required for inflammation resolution. Thus, these two opposing mechanisms provide a fine-tuning control of inflammatory transcript destabilization while maintaining the expression of the negative feedback loops required for efficient inflammation resolution; disruption of this balance can lead to disease.
publishDate 2022
dc.date.none.fl_str_mv 2022
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/53542
http://dx.doi.org/10.7554/eLife.75873
url http://hdl.handle.net/10230/53542
http://dx.doi.org/10.7554/eLife.75873
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Elife. 2022 Apr 20;11:e75873
info:eu-repo/grantAgreement/ES/2PE/BFU2017-83561-P
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv eLife
publisher.none.fl_str_mv eLife
dc.source.none.fl_str_mv reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812455

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