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...

Full description

Saved in:
Bibliographic Details
Published in:eLife 2022-04, Vol.11
Main Authors: Suñer, Clara, Sibilio, Annarita, Martín, Judit, Castellazzi, Chiara Lara, Reina, Oscar, Dotu, Ivan, Caballé, Adrià, Rivas, Elisa, Calderone, Vittorio, Díez, Juana, Nebreda, Angel R, Méndez, Raúl
Format: Article
Language:English
Subjects:
Bone marrow
Cell Biology
CPEB
Feedback
Gene expression
Inflammation
Kinases
Lipopolysaccharides
Macrophages
MAP kinase
MAPK
Messenger RNA
mRNA stability
Polyadenylation
Protein binding
Proteins
RNA Binding Protein
Sepsis
TTP
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.75873