Cot/tpl2-MKK1/2-Erk1/2 controls mTORC1-mediated mRNA translation in Toll-like receptor-activated macrophages
Entity
UAM. Departamento de Medicina Preventiva y Salud Pública y MicrobiologíaPublisher
American Society for Cell BiologyDate
2012-08-01Citation
10.1091/mbc.E12-02-0135
Molecular Biology of the Cell 23.15 (2012): 2982-2992
ISSN
1059-1524 (print); 1939-4586 (online)DOI
10.1091/mbc.E12-02-0135Funded by
This work was supported by SAF 2011-24481 and Mutua Madrileña grants to S.A. and by FIS 2009-80145 and Universidad Autónoma de Madrid CM-CCG10-4911 grants to G.S. PD 0325901 was a gift from Philip Cohen, rapamycin was from Victor Calvo, and the biscitronic pcDNA3rLuc-polIRESfLuc plasmid was generously provided by Alexey BenyumovSubjects
LIM Domain Proteins; Lipopolysaccharides; MAP Kinase Kinase 1; Inbred C57BL; RNA, Messenge; Protein Biosynthesis; MedicinaRights
© 2012 López-Pelaéz et alEsta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-CompartirIgual 4.0 Internacional.
Abstract
Cot/tpl2 is the only MAP3K that activates MKK1/2-Erk1/2 in Toll-like receptor–activated macrophages. Here we show that Cot/tpl2 regulates RSK, S6 ribosomal protein, and 4E-BP phosphorylation after stimulation of bone marrow–derived macrophages with lipopolysaccharide (LPS), poly I:C, or zymosan. The dissociation of the 4E-BP–eIF4E complex, a key event in the cap-dependent mRNA translation initiation, is dramatically reduced in LPS-stimulated Cot/tpl2-knockout (KO) macrophages versus LPS-stimulated wild-type (Wt) macrophages. Accordingly, after LPS activation, increased cap-dependent translation is observed in Wt macrophages but not in Cot/tpl2 KO macrophages. In agreement with these data, Cot/tpl2 increases the polysomal recruitment of the 5´ TOP eEF1α and eEF2 mRNAs, as well as of inflammatory mediator gene–encoding mRNAs, such as tumor necrosis factor α (TNFα), interleukin-6 (IL-6), and KC in LPS-stimulated macrophages. In addition, Cot/tpl2 deficiency also reduces total TNFα, IL-6, and KC mRNA expression in LPS-stimulated macrophages, which is concomitant with a decrease in their mRNA half-lives. Macrophages require rapid fine control of translation to provide an accurate and not self-damaging response to host infection, and our data show that Cot/tpl2 controls inflammatory mediator gene–encoding mRNA translation in Toll-like receptor–activated macrophages
Files in this item
Google Scholar:López-Peláez, Marta
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Fumagalli, Stefano
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Sanz, Carlos
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Herrero, Clara
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Guerra García, María Susana
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Fernández, Margarita Carmen
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Alemany, Susana
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