title: De-ubiquitinating enzyme, USP11, promotes transforming growth factor β-1 signaling through stabilization of transforming growth factor β receptor II.
abstract: The transforming growth factor β-1 (TGFβ-1) signaling pathway plays a central role in the pathogenesis of pulmonary fibrosis. Two TGFβ-1 receptors, TβRI and TβRII, mediate this pathway. TβRI protein stability, as mediated by the ubiquitin/de-ubiquitination system, has been well studied; however, the molecular regulation of TβRII still remains unclear. Here we reveal that a de-ubiquitinating enzyme, USP11, promotes TGFβ-1 signaling through de-ubiquitination and stabilization of TβRII. We elucidate the role that mitoxantrone (MTX), an USP11 inhibitor, has in the attenuation of TGFβ-1 signaling. Inhibition or downregulation of USP11 results in increases in TβRII ubiquitination and reduction of TβRII stability. Subsequently, TGFβ-1 signaling is greatly attenuated, as shown by the decreases in phosphorylation of SMAD2/3 levels as well as that of fibronectin (FN) and smooth muscle actin (SMA). Overexpression of USP11 reduces TβRII ubiquitination and increases TβRII stabilization, thereby elevating phosphorylation of SMAD2/3 and the ultimate expression of FN and SMA. Further, elevated expression of USP11 and TβRII were detected in lung tissues from bleomycin-challenged mice and IPF patients. Therefore, USP11 may contribute to the pathogenesis of pulmonary fibrosis by stabilization of TβRII and promotion of TGFβ-1 signaling. This study provides mechanistic evidence for development of USP11 inhibitors as potential antifibrotic drugs for pulmonary fibrosis.
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Jacko
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.|Department of Anesthesia, The First Affiliated Hospital of Jilin University, Changchun, China.
authors.forename: L
authors.initials: L
authors.lastname: Nan
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.|Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
authors.forename: S
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Tan
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Kass
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001761:Bleomycin; D002460:Cell Line; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000473:pathology; D008810:Mice, Inbred C57BL; D008942:Mitoxantrone / Q000494:pharmacology; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D055550:Protein Stability / Q000187:drug effects; D011658:Pulmonary Fibrosis / Q000378:metabolism / Q000473:pathology; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D013869:Thiolester Hydrolases / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D005353:Fibronectins; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; C101359:USP11 protein, human; C000622145:USP11 protein, mouse; D001761:Bleomycin; D008942:Mitoxantrone; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D013869:Thiolester Hydrolases