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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-04-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/75873 |
| _version_ | 1828169810670780416 |
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| author | Clara Suñer Annarita Sibilio Judit Martín Chiara Lara Castellazzi Oscar Reina Ivan Dotu Adrià Caballé Elisa Rivas Vittorio Calderone Juana Díez Angel R Nebreda Raúl Méndez |
| author_facet | Clara Suñer Annarita Sibilio Judit Martín Chiara Lara Castellazzi Oscar Reina Ivan Dotu Adrià Caballé Elisa Rivas Vittorio Calderone Juana Díez Angel R Nebreda Raúl Méndez |
| author_sort | Clara Suñer |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T02:58:21Z |
| format | Article |
| id | doaj.art-4e3e383266cb49608da7a9a2ea87fedf |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:58:21Z |
| publishDate | 2022-04-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-4e3e383266cb49608da7a9a2ea87fedf2022-12-22T03:50:44ZengeLife Sciences Publications LtdeLife2050-084X2022-04-011110.7554/eLife.75873Macrophage inflammation resolution requires CPEB4-directed offsetting of mRNA degradationClara Suñer0https://orcid.org/0000-0003-2581-8864Annarita Sibilio1Judit Martín2Chiara Lara Castellazzi3Oscar Reina4Ivan Dotu5Adrià Caballé6Elisa Rivas7Vittorio Calderone8Juana Díez9Angel R Nebreda10https://orcid.org/0000-0002-7631-4060Raúl Méndez11https://orcid.org/0000-0002-1952-6905Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, SpainInstitute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, SpainInstitute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, SpainInstitute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, SpainInstitute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, SpainUniversitat Pompeu Fabra, Barcelona, SpainInstitute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, SpainInstitute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, SpainInstitute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, SpainUniversitat Pompeu Fabra, Barcelona, SpainInstitute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, SpainInstitute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, SpainChronic 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.https://elifesciences.org/articles/75873mRNA stabilityRNA Binding ProteinCPEBTTPMAPK |
| spellingShingle | Clara Suñer Annarita Sibilio Judit Martín Chiara Lara Castellazzi Oscar Reina Ivan Dotu Adrià Caballé Elisa Rivas Vittorio Calderone Juana Díez Angel R Nebreda Raúl Méndez Macrophage inflammation resolution requires CPEB4-directed offsetting of mRNA degradation eLife mRNA stability RNA Binding Protein CPEB TTP MAPK |
| title | Macrophage inflammation resolution requires CPEB4-directed offsetting of mRNA degradation |
| title_full | Macrophage inflammation resolution requires CPEB4-directed offsetting of mRNA degradation |
| title_fullStr | Macrophage inflammation resolution requires CPEB4-directed offsetting of mRNA degradation |
| title_full_unstemmed | Macrophage inflammation resolution requires CPEB4-directed offsetting of mRNA degradation |
| title_short | Macrophage inflammation resolution requires CPEB4-directed offsetting of mRNA degradation |
| title_sort | macrophage inflammation resolution requires cpeb4 directed offsetting of mrna degradation |
| topic | mRNA stability RNA Binding Protein CPEB TTP MAPK |
| url | https://elifesciences.org/articles/75873 |
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