Histone deacetylase 2 is phosphorylated, ubiquitinated, and degraded by cigarette smoke

David Adenuga, Hongwei Yao, Thomas H March, JeanClare Seagrave, Irfan Rahman

Research output: Contribution to journalArticlepeer-review


Cigarette smoke (CS)-induced lung inflammation involves the reduction of histone deacetylase 2 (HDAC2) abundance, which is associated with steroid resistance in patients with chronic obstructive pulmonary disease and in individuals with severe asthma who smoke cigarettes. However, the molecular mechanism of CS-mediated reduction of HDAC2 is not clearly known. We hypothesized that HDAC2 is phosphorylated and subsequently degraded by the proteasome in vitro in macrophages (MonoMac6), human bronchial and primary small airway epithelial cells, and in vivo in mouse lungs in response to chronic CS exposure. Cigarette smoke extract (CSE) exposure in MonoMac6 and in bronchial and airway epithelial cells led to phosphorylation of HDAC2 on serine/threonine residues by a protein kinase CK2-mediated mechanism, decreased HDAC2 activity, and increased ubiquitin-proteasome-dependent HDAC2 degradation. CK2 and proteasome inhibitors reversed CSE-mediated HDAC2 degradation, whereas serine/threonine phosphatase inhibitor, okadaic acid, caused phosphorylation and subsequent ubiquitination of HDAC2. CS-induced HDAC2 phosphorylation was detected in mouse lungs from 2 weeks to 4 months of CS exposure, and mice showed significantly lower lung HDAC2 levels. Thus, CS-mediated down-regulation of HDAC2 in human macrophages and lung epithelial cells in vitro and in mouse lung in vivo involves the induction of serine/threonine phosphorylation and proteasomal degradation, which may have implications for steroid resistance and abnormal inflammation caused by cigarette smoke.
Original languageEnglish
Pages (from-to)464-73
Number of pages10
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Issue number4
Publication statusPublished - Apr 2009


  • Animals
  • Bronchi
  • Casein Kinase II
  • Cell Line
  • Epithelial Cells
  • Female
  • Histone Deacetylase 2
  • Histone Deacetylases
  • humans
  • Male
  • MICE
  • Phosphorylation
  • Proteasome Endopeptidase Complex
  • Protein Processing, Post-Translational
  • Repressor Proteins
  • Smoke
  • Smoking
  • Time Factors
  • Tobacco
  • Ubiquitin
  • Ubiquitination


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