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

The Journal of Clinical Investigation
Jeong-Han KangEdward B Leof

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.

References

Jun 1, 1992·Molecular Reproduction and Development·J MassaguéJ L Wrana
Feb 13, 2002·American Journal of Physiology. Lung Cellular and Molecular Physiology·Jingsong ZhaoDavid Warburton
Dec 4, 2002·Nature Reviews. Molecular Cell Biology·Carolyn A Worby, Jack E Dixon
Jul 16, 2003·Proceedings of the National Academy of Sciences of the United States of America·Anita B Roberts, Lalage M Wakefield
Nov 13, 2003·Molecular and Cellular Biology·Mark C WilkesEdward B Leof
Jul 31, 2004·Nature Genetics·Rosemary J Akhurst
Nov 3, 2004·The Journal of Clinical Investigation·Craig E DanielsEdward B Leof
Jan 5, 2005·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Shinong WangRaimund Hirschberg
Jan 7, 2005·Traffic·Jez CarltonPete Cullen
Mar 19, 2005·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Rebecca L Elliott, Gerard C Blobe
Aug 18, 2005·Journal of Cell Science·Aristidis Moustakas, Carl-Henrik Heldin
Oct 11, 2005·Annual Review of Cell and Developmental Biology·Xin-Hua Feng, Rik Derynck
Jan 18, 2006·American Journal of Respiratory and Critical Care Medicine·Nveed I ChaudharyJohn E Park
Jan 24, 2007·Proceedings of the National Academy of Sciences of the United States of America·Karen BadourKatherine A Siminovitch
Mar 3, 2007·The Journal of Clinical Investigation·Thomas A Wynn
May 9, 2007·Frontiers in Bioscience : a Journal and Virtual Library·Marcel Verges
Jun 26, 2007·World Journal of Gastroenterology : WJG·Franck Verrecchia, Alain Mauviel
Aug 31, 2007·Journal of Cellular Biochemistry·Rod A Rahimi, Edward B Leof
Mar 26, 2008·Molecular Therapy : the Journal of the American Society of Gene Therapy·Matan RapoportHaya Lorberboum-Galski
Dec 19, 2008·Journal of Cell Science·Richard Lundmark, Sven R Carlsson
Dec 31, 2008·Cell Research·Caroline S Hill
Feb 25, 2009·Current Opinion in Cell Biology·Carl-Henrik HeldinAristidis Moustakas
Mar 17, 2009·Biochemical and Biophysical Research Communications·Hyo Sang Jang, Jeffrey A Greenwood
Mar 18, 2009·Developmental Cell·Mary Y Wu, Caroline S Hill
Feb 4, 2010·Annals of Internal Medicine·Joel RosenbloomSergio A Jimenez
Feb 16, 2010·Cellular Signalling·Catherine E GatzaGerard C Blobe
Apr 2, 2010·The Journal of Biological Chemistry·Christopher F HarrisonAndrew F Hill
May 25, 2010·Nature Reviews. Cancer·Hiroaki Ikushima, Kohei Miyazono
Jul 3, 2010·Journal of the American Society of Nephrology : JASN·Xiao Ming MengHui Yao Lan
Sep 16, 2010·Cancer Research·Mahefatiana AndrianifahananaEdward B Leof
Oct 25, 2011·Free Radical Biology & Medicine·Jingke GuoPingfan Rao
Mar 28, 2012·Current Opinion in Rheumatology·Christian BeyerJörg H W Distler

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Citations

Dec 1, 2017·Acta Biochimica Et Biophysica Sinica·Feng XieLong Zhang
Apr 28, 2018·International Journal of Molecular Sciences·Laia CajaIsabel Fabregat
Apr 12, 2019·American Journal of Respiratory and Critical Care Medicine·Dianhua Jiang, Jiurong Liang
Nov 21, 2019·Biomolecules·Linh Khanh HuynhPeter Ten Dijke
Feb 19, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Danielle M HernandezEdward B Leof
Mar 7, 2020·Expert Opinion on Drug Delivery·Larissa Gomes Dos Reis, Daniela Traini
Jun 11, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Malay ChoudhuryEdward B Leof
Dec 11, 2019·Lasers in Surgery and Medicine·Dimakatso R MokoenaHeidi Abrahamse
Jan 8, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Jeong-Han KangEdward B Leof
Jul 8, 2020·International Journal of Molecular Sciences·Sujin KimWeon Kuu Chung
Feb 4, 2021·The Journal of Gene Medicine·Songzi ZhangXiaodong Song
Feb 19, 2021·Ecotoxicology and Environmental Safety·Yan LiChunhui Ni
Aug 3, 2021·Evidence-based Complementary and Alternative Medicine : ECAM·Yun YangWen-Juan Gan
Dec 23, 2021·JCI Insight·Shailza SharmaCarol Feghali-Bostwick
Dec 1, 2021·The FEBS Journal·Juan HuangJian Yang

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Methods Mentioned

BETA
pull-down
nuclear translocation
PCR
transfection
reverse-transcription PCR
Assay

Software Mentioned

GraphPad Prism

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