title: USP17-mediated deubiquitination and stabilization of HDAC2 in cigarette smoke extract-induced inflammation.
abstract: Histone deacetylase HDAC2 regulates genes transcription via removing the acetyl group from histones. Glucocorticoids, the most potent anti-inflammatory treatment available for inflammatory diseases, inhibit the expression of inflammatory genes by recruiting HDAC2 to activated genes. In the lungs of patients who smoke and have chronic obstructive pulmonary disease (COPD) or asthma, glucocorticoids are not effective enough to suppress airway inflammation, which is so called "glucocorticoid resistance", due to decreased HDAC2 level caused by cigarette smoke. We report that the ubiquitin-specific protease USP17 interacts with HDAC2. USP17 deubiquitinates and stabilizes the protein level of HDAC2. In cigarette smoke extract-exposed airway epithelial cells and macrophages, HDAC2 is excessively ubiquitinated and degraded in the proteasome attributed to low expression of USP17. Furthermore, over-expression of USP17 blocks the destruction of HDAC2 induced by cigarette smoke extract. These results provide a new insight into the mechanisms of glucocorticoid resistance in airway inflammatory disease. Small molecules which can specifically induce the expression of USP17 might be useful in reversing glucocorticoid resistance.
authors.affiliation: Department of Pulmonary Medicine, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai 200025, P. R China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Song
authors.affiliation: Department of Pulmonary Medicine, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai 200025, P. R China.
authors.forename: Lianqin
authors.initials: L
authors.lastname: Tao
authors.affiliation: Key Laboratory of Molecular Virology and Immunology, Unit of Molecular Immunology, Institute Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences (CAS) Shanghai 200031, P. R China.
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Pulmonary Medicine, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai 200025, P. R China.
authors.forename: Lina
authors.initials: L
authors.lastname: Pan
authors.affiliation: Department of Pulmonary Medicine, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai 200025, P. R China.
authors.forename: Jimin
authors.initials: J
authors.lastname: Hao
authors.affiliation: Department of Pulmonary Medicine, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai 200025, P. R China.
authors.forename: Yingmeng
authors.initials: Y
authors.lastname: Ni
authors.affiliation: Key Laboratory of Molecular Virology and Immunology, Unit of Molecular Immunology, Institute Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences (CAS) Shanghai 200031, P. R China.
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.affiliation: Key Laboratory of Molecular Virology and Immunology, Unit of Molecular Immunology, Institute Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences (CAS) Shanghai 200031, P. R China.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Pulmonary Medicine, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai 200025, P. R China.
authors.forename: Guochao
authors.initials: G
authors.lastname: Shi
mesh_terms: D045744:Cell Line, Tumor; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D004795:Enzyme Stability; D004847:Epithelial Cells / Q000201:enzymology; D057809:HEK293 Cells; D056464:Histone Deacetylase 2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000201:enzymology*; D008264:Macrophages / Q000201:enzymology; D011014:Pneumonia / Q000201:enzymology* / Q000209:etiology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects*; D013997:Time Factors; D014162:Transfection; D054875:Ubiquitination
chemical_list: D012906:Smoke; D010450:Endopeptidases; C484854:USP17L2 protein, human; D046988:Proteasome Endopeptidase Complex; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2
keywords: HDAC2; USP17; cigarette smoke extract; deubiquitination; glucocorticoid resistance