Microtubule acetylation amplifies p38 kinase signalling and anti-inflammatory IL-10 production

Nat Commun. 2014 Mar 17;5:3479. doi: 10.1038/ncomms4479.

Abstract

Reversible acetylation of α-tubulin is an evolutionarily conserved modification in microtubule networks. Despite its prevalence, the physiological function and regulation of microtubule acetylation remain poorly understood. Here we report that macrophages challenged by bacterial lipopolysaccharides (LPS) undergo extensive microtubule acetylation. Suppression of LPS-induced microtubule acetylation by inactivating the tubulin acetyltransferase, MEC17, profoundly inhibits the induction of anti-inflammatory interleukin-10 (IL-10), a phenotype effectively reversed by an acetylation-mimicking α-tubulin mutant. Conversely, elevating microtubule acetylation by inhibiting the tubulin deacetylase, HDAC6, or stabilizing microtubules via Taxol stimulates IL-10 hyper-induction. Supporting the anti-inflammatory function of microtubule acetylation, HDAC6 inhibition significantly protects mice from LPS toxicity. In HDAC6-deficient macrophages challenged by LPS, p38 kinase signalling becomes selectively amplified, leading to SP1-dependent IL-10 transcription. Remarkably, the augmented p38 signalling is suppressed by MEC17 inactivation. Our findings identify reversible microtubule acetylation as a kinase signalling modulator and a key component in the inflammatory response.

MeSH terms

  • Acetylation
  • Animals
  • Cell Line
  • Histone Deacetylase 6
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism
  • Interleukin-10 / immunology*
  • Lipopolysaccharides / immunology
  • Macrophages / enzymology
  • Macrophages / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microtubules / immunology
  • Microtubules / metabolism*
  • Signal Transduction
  • Tubulin / immunology
  • Tubulin / metabolism
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • Lipopolysaccharides
  • Tubulin
  • Interleukin-10
  • p38 Mitogen-Activated Protein Kinases
  • Hdac6 protein, mouse
  • Histone Deacetylase 6
  • Histone Deacetylases