Macrophage inflammation resolution requires CPEB4-directed offsetting of mRNA degradation
- Institute for Research in Biomedicine (IRB), Spain
- Universitat Pompeu Fabra, Spain
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 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.
Data availability
Raw data for RIP-seq and RNA-seq datasets are available in GEO (accession number GSE160191 and GSE160346, respectively). Numerical data from genome-wide experiments and motif analysis are available in supplementary tables 1-6. All blots shown and used for quantifications have been provided as source data.Scripts are available as Supplementary files 9.
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Macrophage inflammation resolution requires CPEB4-directed offsetting of mRNA degradationNCBI Gene Expression Omnibus, GSE160191.
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Macrophage inflammation resolution requires CPEB4-directed offsetting of mRNA degradationNCBI Gene Expression Omnibus, GSE160346.
Article and author information
Author details
Funding
Ministerio de Asuntos Económicos y Transformación Digital, Gobierno de España (BFU2017-83561-P)
- Raúl Méndez
BBVA Foundation
- Raúl Méndez
la Caixa" Foundation "
- Raúl Méndez
Fundación Científica Asociación Española Contra el Cáncer
- Raúl Méndez
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations of the Euopean Directive 2010/63/EU on the protection of animals used for scientific purposes. All experimental protocols were approved by the Animal Ethics Committee at the Parc Cientific de Barcelona.
Copyright
© 2022, Suñer et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Macrophage inflammation resolution requires CPEB4-directed offsetting of mRNA degradation
eLife 11:e75873.
https://doi.org/10.7554/eLife.75873
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