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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • 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 Date

  • November 1, 2014

Published In

Volume / Issue

  • 25 / 21

Start / End Page

  • 3300 - 3307

PubMed ID

  • 25187650

Pubmed Central ID

  • PMC4214777

Electronic International Standard Serial Number (EISSN)

  • 1939-4586

Digital Object Identifier (DOI)

  • 10.1091/mbc.E13-12-0757


  • eng

Conference Location

  • United States