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 and Tso-Pang Yao ()
Additional contact information
Bin Wang: DUMC, Box 3813
Yan-Hua Rao: DUMC, Box 3813
Makoto Inoue: DUMC, Box 3010
Rui Hao: DUMC, Box 3813
Chun-Hsiang Lai: DUMC, Box 3813
David Chen: DUMC, Box 3813
Stacey L. McDonald: Duke University, 124 Science Drive
Moon-Chang Choi: DUMC, Box 3813
Qiu Wang: Duke University, 124 Science Drive
Mari L. Shinohara: DUMC, Box 3010
Tso-Pang Yao: DUMC, Box 3813

Nature Communications, 2014, vol. 5, issue 1, 1-7

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4479

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