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.
-
Macrophage inflammation resolution requires CPEB4-directed offsetting of mRNA degradationNCBI Gene Expression Omnibus, GSE160191.
-
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.
Metrics
-
- 1,406
- views
-
- 308
- downloads
-
- 17
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
