Macrophage inflammation resolution requires CPEB4-directed offsetting of mRNA degradation

Mostra el registre complet Registre parcial de l'ítem

• dc.contributor.author Suñer, Clara
• dc.contributor.author Sibilio, Annarita
• dc.contributor.author Martín, Judit
• dc.contributor.author Castellazzi, Chiara Lara
• dc.contributor.author Reina García, Óscar, 1976-
• dc.contributor.author Dotu, Ivan
• dc.contributor.author Caballé, Adrià
• dc.contributor.author Rivas, Elisa
• dc.contributor.author Calderone, Vittorio
• dc.contributor.author Díez Antón, Juana, 1962-
• dc.contributor.author Nebreda, Ángel R.
• dc.contributor.author Méndez de la Iglesia, Raúl
• dc.date.accessioned 2022-06-21T06:09:21Z
• dc.date.available 2022-06-21T06:09:21Z
• dc.date.issued 2022
• dc.description.abstract 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.
• dc.description.sponsorship 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).
• dc.format.mimetype application/pdf
• dc.identifier.citation Suñer C, Sibilio A, Martín J, Castellazzi CL, Reina O, Dotu I, Caballé A, Rivas E, Calderone V, Díez J, Nebreda AR, Méndez R. Macrophage inflammation resolution requires CPEB4-directed offsetting of mRNA degradation. Elife. 2022 Apr 20;11:e75873. DOI: 10.7554/eLife.75873
• dc.identifier.doi http://dx.doi.org/10.7554/eLife.75873
• dc.identifier.issn 2050-084X
• dc.identifier.uri http://hdl.handle.net/10230/53542
• dc.language.iso eng
• dc.publisher eLife
• dc.relation.ispartof Elife. 2022 Apr 20;11:e75873
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BFU2017-83561-P
• dc.rights © 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.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword CPEB
• dc.subject.keyword MAPK
• dc.subject.keyword RNA Binding Protein
• dc.subject.keyword TTP
• dc.subject.keyword Cell biology
• dc.subject.keyword mRNA stability
• dc.subject.keyword Mouse
• dc.title Macrophage inflammation resolution requires CPEB4-directed offsetting of mRNA degradation
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion