title: Glycolysis-dependent histone deacetylase 4 degradation regulates inflammatory cytokine production.
abstract: 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.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710 Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710.
authors.forename: Ting-Yu
authors.initials: TY
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710.
authors.forename: Chun-Hsiang
authors.initials: CH
authors.lastname: Lai
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710.
authors.forename: Yan-hua
authors.initials: YH
authors.lastname: Rao
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710.
authors.forename: Moon-Chang
authors.initials: MC
authors.lastname: Choi
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27710.
authors.forename: Jen-Tsan
authors.initials: JT
authors.lastname: Chi
authors.affiliation: Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Jian-wu
authors.initials: JW
authors.lastname: Dai
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Rathmell
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710 yao00001@mc.duke.edu.
authors.forename: Tso-Pang
authors.initials: TP
authors.lastname: Yao
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006019:Glycolysis / Q000187:drug effects / Q000502:physiology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000378:metabolism; D009154:Mutation; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D038362:Glycogen Synthase Kinase 3; D053148:Caspase 3; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases