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Glycolysis-dependent histone deacetylase 4 degradation regulates inflammatory cytokine production.

Publication ,  Journal Article
Wang, B; Liu, T-Y; Lai, C-H; Rao, Y-H; Choi, M-C; Chi, J-T; Dai, J-W; Rathmell, JC; Yao, T-P
Published in: Mol Biol Cell
November 1, 2014

Activation of the inflammatory response is accompanied by a metabolic shift to aerobic glycolysis. Here we identify histone deacetylase 4 (HDAC4) as a new component of the immunometabolic program. We show that HDAC4 is required for efficient inflammatory cytokine production activated by lipopolysaccharide (LPS). Surprisingly, prolonged LPS treatment leads to HDAC4 degradation. LPS-induced HDAC4 degradation requires active glycolysis controlled by GSK3β and inducible nitric oxide synthase (iNOS). Inhibition of GSK3β or iNOS suppresses nitric oxide (NO) production, glycolysis, and HDAC4 degradation. We present evidence that sustained glycolysis induced by LPS treatment activates caspase-3, which cleaves HDAC4 and triggers its degradation. Of importance, a caspase-3-resistant mutant HDAC4 escapes LPS-induced degradation and prolongs inflammatory cytokine production. Our findings identify the GSK3β-iNOS-NO axis as a critical signaling cascade that couples inflammation to metabolic reprogramming and a glycolysis-driven negative feedback mechanism that limits inflammatory response by triggering HDAC4 degradation.

Duke Scholars

Published In

Mol Biol Cell

DOI

EISSN

1939-4586

Publication Date

November 1, 2014

Volume

25

Issue

21

Start / End Page

3300 / 3307

Location

United States

Related Subject Headings

  • Ribosomal Protein S6 Kinases, 70-kDa
  • Nitric Oxide Synthase Type II
  • Nitric Oxide
  • Mutation
  • Microglia
  • Mice
  • Macrophages
  • Lipopolysaccharides
  • Inflammation
  • Histone Deacetylases
 

Citation

APA
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ICMJE
MLA
NLM
Wang, B., Liu, T.-Y., Lai, C.-H., Rao, Y.-H., Choi, M.-C., Chi, J.-T., … Yao, T.-P. (2014). Glycolysis-dependent histone deacetylase 4 degradation regulates inflammatory cytokine production. Mol Biol Cell, 25(21), 3300–3307. https://doi.org/10.1091/mbc.E13-12-0757
Wang, Bin, Ting-Yu Liu, Chun-Hsiang Lai, Yan-hua Rao, Moon-Chang Choi, Jen-Tsan Chi, Jian-wu Dai, Jeffrey C. Rathmell, and Tso-Pang Yao. “Glycolysis-dependent histone deacetylase 4 degradation regulates inflammatory cytokine production.Mol Biol Cell 25, no. 21 (November 1, 2014): 3300–3307. https://doi.org/10.1091/mbc.E13-12-0757.
Wang B, Liu T-Y, Lai C-H, Rao Y-H, Choi M-C, Chi J-T, et al. Glycolysis-dependent histone deacetylase 4 degradation regulates inflammatory cytokine production. Mol Biol Cell. 2014 Nov 1;25(21):3300–7.
Wang, Bin, et al. “Glycolysis-dependent histone deacetylase 4 degradation regulates inflammatory cytokine production.Mol Biol Cell, vol. 25, no. 21, Nov. 2014, pp. 3300–07. Pubmed, doi:10.1091/mbc.E13-12-0757.
Wang B, Liu T-Y, Lai C-H, Rao Y-H, Choi M-C, Chi J-T, Dai J-W, Rathmell JC, Yao T-P. Glycolysis-dependent histone deacetylase 4 degradation regulates inflammatory cytokine production. Mol Biol Cell. 2014 Nov 1;25(21):3300–3307.

Published In

Mol Biol Cell

DOI

EISSN

1939-4586

Publication Date

November 1, 2014

Volume

25

Issue

21

Start / End Page

3300 / 3307

Location

United States

Related Subject Headings

  • Ribosomal Protein S6 Kinases, 70-kDa
  • Nitric Oxide Synthase Type II
  • Nitric Oxide
  • Mutation
  • Microglia
  • Mice
  • Macrophages
  • Lipopolysaccharides
  • Inflammation
  • Histone Deacetylases