Over-expression of prothymosin-α antagonizes TGFβ signalling to promote the development of emphysema

Bing Hua Su, Yau Lin Tseng, Gia Shing Shieh, Yi Cheng Chen, Pensee Wu, Ai Li Shiau, Chao Liang Wu

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)412-422
Number of pages11
JournalJournal of Pathology
Volume238
Issue number3
DOIs
Publication statusPublished - Feb 1 2016
Externally publishedYes

Fingerprint

Emphysema
Transforming Growth Factors
Tissue Inhibitor of Metalloproteinase-3
Matrix Metalloproteinase 3
Histone Deacetylases
Acetylation
Matrix Metalloproteinases
Tissue Inhibitor of Metalloproteinases
Matrix Metalloproteinase Inhibitors
Histones
Lung
Chronic Obstructive Pulmonary Disease
Elasticity
Nuclear Proteins
Epigenomics
Smoke
Tobacco Products
Transgenic Mice
Cytoplasm
Homeostasis

Keywords

  • COPD
  • emphysema
  • HDAC
  • prothymosin α
  • Smad7
  • TGFβ
  • TIMP-3

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Over-expression of prothymosin-α antagonizes TGFβ signalling to promote the development of emphysema. / Su, Bing Hua; Tseng, Yau Lin; Shieh, Gia Shing; Chen, Yi Cheng; Wu, Pensee; Shiau, Ai Li; Wu, Chao Liang.

In: Journal of Pathology, Vol. 238, No. 3, 01.02.2016, p. 412-422.

Research output: Contribution to journalArticle

Su, Bing Hua ; Tseng, Yau Lin ; Shieh, Gia Shing ; Chen, Yi Cheng ; Wu, Pensee ; Shiau, Ai Li ; Wu, Chao Liang. / Over-expression of prothymosin-α antagonizes TGFβ signalling to promote the development of emphysema. In: Journal of Pathology. 2016 ; Vol. 238, No. 3. pp. 412-422.
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