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TPL2 kinase expression is regulated by the p38γ/p38δ-dependent association of aconitase-1 with TPL2 mRNA

Alejandra Escós1, José Martín-Gómez1, Diego González-Romero1

  • 1Department of Immunology and Oncology, Centro Nacional de Biotecnología-Consejo Superior de Investigaciones Científicas (CNB/CSIC) Campus Universidad Autónoma de Madrid (UAM), Madrid, 28049 Spain.

Proceedings of the National Academy of Sciences of the United States of America
|August 22, 2022
PubMed

Insights

p38γ/p38δ kinases regulate inflammation by controlling tumor progression locus 2 (TPL2) protein levels. They enhance TPL2 stability and translation, revealing a novel posttranscriptional regulation mechanism crucial for innate immunity.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Signaling

Background:

  • p38γ and p38δ (p38γ/p38δ) kinases are key regulators of inflammation.
  • Tumor progression locus 2 (TPL2) is a critical mediator in myeloid cell-driven inflammatory responses.

Purpose of the Study:

  • To elucidate the posttranscriptional regulatory mechanisms by which p38γ/p38δ control TPL2 expression.
  • To investigate the role of p38γ/p38δ in TPL2 protein stability and mRNA translation.

Main Methods:

  • Analysis of TPL2 protein and mRNA levels in p38γ/δ-deficient cells and tissues.
  • Co-immunoprecipitation assays to study protein complex formation.
  • Assessment of mRNA translation efficiency and protein stability.
  • Functional studies involving aconitase-1 (ACO1) manipulation.

Main Results:

  • TPL2 protein levels are significantly reduced in p38γ/δ-/- cells, independent of mRNA levels.
  • p38γ/p38δ interact with the TPL2/A20 Binding Inhibitor of NF-κB2 (ABIN2)/Nuclear Factor κB1p105 (NF-κB1p105) complex, stabilizing TPL2 protein.
  • p38γ/p38δ modulate TPL2 mRNA translation by regulating the repressor activity of the TPL2 3' Untranslated Region (UTR) via aconitase-1 (ACO1).
  • p38δ directly binds ACO1, and its reintroduction restores TPL2 protein levels by alleviating translational repression.

Conclusions:

  • p38γ/p38δ control TPL2 expression through a dual posttranscriptional mechanism involving protein stabilization and translational control.
  • This regulation is mediated by interactions with the TPL2 complex and modulation of ACO1-dependent translational repression.
  • The findings reveal a novel regulatory pathway for TPL2, highlighting its significance in innate immunity and potential relevance in physiopathology.
Keywords:
3′UTRACO1TPL2mRNA translationp38γ/p38δ-MAPK

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