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

Bin Wang, Yan Hua Rao, Makoto Inoue, Rui Hao, Chun Hsiang Lai, David Chen, Stacey L. McDonald, Moon Chang Choi, Qiu Wang, Mari L. Shinohara, Tso Pang Yao

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number3479
JournalNature communications
Volume5
DOIs
StatePublished - Mar 17 2014

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Wang, B., Rao, Y. H., Inoue, M., Hao, R., Lai, C. H., Chen, D., McDonald, S. L., Choi, M. C., Wang, Q., Shinohara, M. L., & Yao, T. P. (2014). Microtubule acetylation amplifies p38 kinase signalling and anti-inflammatory IL-10 production. Nature communications, 5, [3479]. https://doi.org/10.1038/ncomms4479