期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 127, 期 7, 页码 2541-2554出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI88696
关键词
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资金
- Public Health Service from the National Institute of General Medical Sciences [GM-55816, GM-54200]
- Mayo Brain SPORE [CA-108961]
- Caerus Foundation
- Mayo Foundation
TGF-beta 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-beta activity in murine cells and human lung fibroblasts as well as in vivo with no demonstrable toxicity. TGF-beta 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-beta'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-beta.
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