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Cot/tpl2-MKK1/2-Erk1/2 controls mTORC1-mediated mRNA translation in Toll-like receptor-activated macrophages

Marta López-Pelaéz1, Stefano Fumagalli, Carlos Sanz

  • 1Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas, 28029 Madrid, Spain.

Molecular Biology of the Cell
|June 8, 2012
PubMed

Insights

Cot/tpl2 kinase controls mRNA translation in macrophages responding to infection. This kinase is crucial for initiating cap-dependent translation of inflammatory genes, impacting immune responses.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • Cot/tpl2 is a unique MAP3K activating MKK1/2-Erk1/2 in Toll-like receptor-activated macrophages.
  • Macrophages require precise translation control for effective and safe immune responses.

Purpose of the Study:

  • To investigate the role of Cot/tpl2 in regulating mRNA translation and inflammatory mediator production in macrophages.
  • To elucidate the impact of Cot/tpl2 on cap-dependent translation initiation and inflammatory gene expression.

Main Methods:

  • Stimulation of bone marrow-derived macrophages with lipopolysaccharide (LPS), poly I:C, or zymosan.
  • Analysis of protein phosphorylation (RSK, S6, 4E-BP) and mRNA translation using Cot/tpl2-knockout (KO) and wild-type (Wt) macrophages.
  • Measurement of inflammatory mediator mRNA expression (TNFα, IL-6, KC) and mRNA half-lives.

Main Results:

  • Cot/tpl2 regulates RSK, S6 ribosomal protein, and 4E-BP phosphorylation following TLR stimulation.
  • Cot/tpl2 deficiency impairs the dissociation of the 4E-BP-eIF4E complex, reducing cap-dependent translation initiation.
  • Cot/tpl2 enhances polysomal recruitment of translation initiation factors and inflammatory mRNAs (TNFα, IL-6, KC).
  • Cot/tpl2 deficiency decreases inflammatory gene expression and mRNA half-lives in LPS-stimulated macrophages.

Conclusions:

  • Cot/tpl2 is essential for regulating cap-dependent translation of inflammatory mediator mRNAs in Toll-like receptor-activated macrophages.
  • Cot/tpl2 plays a critical role in controlling the magnitude and kinetics of inflammatory responses by modulating mRNA translation and stability.

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