Glycolysis-dependent histone deacetylase 4 degradation regulates inflammatory cytokine production.
Published
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
- 25187650
Electronic International Standard Serial Number (EISSN)
- 1939-4586
Digital Object Identifier (DOI)
- 10.1091/mbc.E13-12-0757
Language
- eng
Conference Location
- United States