Main Manuscript for Macrophage inflammation resolution requires CPEB4-directed offsetting of mRNA degradation

• Main Authors: Caballé, A. (Author), Calderone, V. (Author), Castellazzi, C.L (Author), Díez, J. (Author), Dotu, I. (Author), Martín, J. (Author), Méndez, R. (Author), Nebreda, A.R (Author), Reina, O. (Author), Rivas, E. (Author), Sibilio, A. (Author), Suñer, C. (Author)
• Format: Article
• Language: English
• Published: eLife Sciences Publications Ltd 2022
• Subjects: CPEBs; MAPK signaling; mRNA stability; RNA binding protein; TTP
• Online Access: View Fulltext in Publisher
• ISBN: 2050084X (ISSN)
• DOI: 10.7554/eLife.75873

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 antiinflammatory 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 LPSinduced 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. © 2022, eLife Sciences Publications Ltd. All rights reserved.