Over-expression of prothymosin-α antagonizes TGFβ signalling to promote the development of emphysema.
Emphysema, a major consequence of chronic obstructive pulmonary disease (COPD), is characterized by the permanent airflow restriction resulting from enlargement of alveolar airspace and loss of lung elasticity. Transforming growth factor-β (TGFβ) signalling regulates the balance of matrix metalloproteinase (MMP)/tissue inhibitor of matrix metalloproteinase (TIMP) to control matrix homeostasis. Patients with COPD have dysregulated TGFβ signalling and reduced histone deacetylase (HDAC) activity through epigenetic up-regulation of histone acetylation in the promoters of pro-inflammatory genes. However, the potential link between decreased HDAC activity and dysregulated TGFβ signalling in emphysema pathogenesis remains to be determined. Prothymosin α (ProT), a highly conserved acidic nuclear protein, plays a role in the acetylation of histone and non-histone proteins. The aim of this study was to test the hypothesis that ProT inhibits TGFβ-Smad signalling through Smad7, thereby contributing to emphysema pathogenesis. We show that ProT enhances Smad7 acetylation by decreasing its association with HDAC and thereby down-regulates TGFβ-Smad signalling. ProT caused an imbalance between MMP and TIMP through acetylated Smad7 in favour of MMP expression. In addition to interfering with R-Smad activation and targeting receptors for degradation in the cytoplasm, acetylated Smad7 potentiated by ProT competitively antagonized binding of the pSmad2/3-Smad4 complex to the TIMP-3 promoter, resulting in reduced TIMP-3 expression. These effects were detected in ProT-over-expressing cells, lungs of ProT transgenic mice displaying an emphysema phenotype and in emphysema patients. Importantly, increased Smad7 and reduced TIMP-3 were found in the lungs of emphysema patients and mice with cigarette smoke extract (CSE)-induced emphysema. Such effects could be abrogated by silencing endogenous ProT expression. Collectively, our results uncover acetylated Smad7 regulated by ProT as an important determinant in dysregulated TGFβ signalling that contributes to emphysema pathogenesis.
Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Bing-Hua
BH
Su
Division of Thoracic Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Yau-Lin
YL
Tseng
Department of Urology, Tainan Hospital, Ministry of Health and Welfare, Tainan, Taiwan.
Gia-Shing
GS
Shieh
Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Yi-Cheng
YC
Chen
Institute for Science and Technology in Medicine, Keele University, UK.
Pensee
P
Wu
Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Ai-Li
AL
Shiau
Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Chao-Liang
CL
Wu
D000107:Acetylation; D000818:Animals; D016022:Case-Control Studies; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011498:Protein Precursors / Q000378:metabolism*; D011656:Pulmonary Emphysema / Q000209:etiology*; D015398:Signal Transduction / Q000502:physiology; D051906:Smad7 Protein / Q000378:metabolism; D013947:Thymosin / Q000031:analogs & derivatives* / Q000378:metabolism; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*
D011498:Protein Precursors; C497806:SMAD7 protein, human; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D019717:Tissue Inhibitor of Metalloproteinase-3; D016212:Transforming Growth Factor beta; C040782:prothymosin alpha; D013947:Thymosin; D020782:Matrix Metalloproteinases; D006655:Histone Deacetylases
COPD; HDAC; Smad7; TGFβ; TIMP-3; emphysema; prothymosin α