Cell-penetrating peptides selectively targeting SMAD3 inhibit profibrotic TGF-β signaling

Jeong Han Kang, Mi Yeon Jung, Xueqian Yin, Mahefatiana Andrianifahanana, Danielle M. Hernandez, Edward B Leof

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

TGF-β is considered a master switch in the pathogenesis of organ fibrosis. The primary mediators of this activity are the SMAD proteins, particularly SMAD3. In the current study, we have developed a cell-penetrating peptide (CPP) conjugate of the HIV TAT protein that is fused to an aminoterminal sequence of sorting nexin 9 (SNX9), which was previously shown to bind phosphorylated SMAD3 (pSMAD3). We determined that specifically preventing the nuclear import of pSMAD3 using the TAT-SNX9 peptide inhibited profibrotic TGF-β activity in murine cells and human lung fibroblasts as well as in vivo with no demonstrable toxicity. TGF-β signaling mediated by pSMAD2, bone morphogenetic protein 4 (BMP4), EGF, or PDGF was unaffected by the TAT-SNX9 peptide. Furthermore, while the TAT-SNX9 peptide prevented TGF-β's profibrotic activity in vitro as well as in 2 murine treatment models of pulmonary fibrosis, a 3-amino acid point mutant that was unable to bind pSMAD3 proved ineffective. These findings indicate that specifically targeting pSMAD3 can ameliorate both the direct and indirect fibroproliferative actions of TGF-β.

Original languageEnglish (US)
Pages (from-to)2541-2554
Number of pages14
JournalJournal of Clinical Investigation
Volume127
Issue number7
DOIs
StatePublished - Jun 30 2017

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Sorting Nexins
Cell-Penetrating Peptides
Peptides
Bone Morphogenetic Protein 4
Human Immunodeficiency Virus Proteins
Cell Nucleus Active Transport
Pulmonary Fibrosis
Epidermal Growth Factor
Fibrosis
Fibroblasts
Amino Acids
Lung
Proteins

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Cell-penetrating peptides selectively targeting SMAD3 inhibit profibrotic TGF-β signaling. / Kang, Jeong Han; Jung, Mi Yeon; Yin, Xueqian; Andrianifahanana, Mahefatiana; Hernandez, Danielle M.; Leof, Edward B.

In: Journal of Clinical Investigation, Vol. 127, No. 7, 30.06.2017, p. 2541-2554.

Research output: Contribution to journalArticle

Kang, Jeong Han ; Jung, Mi Yeon ; Yin, Xueqian ; Andrianifahanana, Mahefatiana ; Hernandez, Danielle M. ; Leof, Edward B. / Cell-penetrating peptides selectively targeting SMAD3 inhibit profibrotic TGF-β signaling. In: Journal of Clinical Investigation. 2017 ; Vol. 127, No. 7. pp. 2541-2554.
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