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.

journal_name

Mol Biol Cell

authors

Wang B,Liu TY,Lai CH,Rao YH,Choi MC,Chi JT,Dai JW,Rathmell JC,Yao TP

doi

10.1091/mbc.E13-12-0757

subject

Has Abstract

pub_date

2014-11-01 00:00:00

pages

3300-7

issue

21

eissn

1059-1524

issn

1939-4586

pii

mbc.E13-12-0757

journal_volume

25

pub_type

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