Background Protein stability is regulated by ubiquitination and deubiquitination. The ubiquitin-deubiquitination system contributes to the regulation of tumor growth factor β1 (TGFβ1) signaling. TGFβ1 mediates its signaling and pro-fibrotic effects through binding to its receptors, TGFβ receptor I (TβRI) and TβRII. Here we reveal that deubiquitinating enzyme USP11 regulates TGFβ1 signaling through stabilization of TβRII.
Methods and Results Bleomycin-induced pulmonary fibrosis is a wildly used murine model of pulmonary fibrosis. Analysis of murine lung tissue lysates from 3 weeks of bleomycin challenge revealed that USP11 levels were elevated in lung tissues from bleomycin-challenged mice. TGFβ1 plays a critical role in the pathogenesis of pulmonary fibrosis. TGFβ1 treatment of human lung fibroblast cells (HLF) induced tyrosine phosphorylation of USP11. To investigate the effect of USP11 in the TGFβ1 signaling, HLF cells were transfected with USP11 shRNA. USP11 shRNA reduced USP11 levels as well as TβRII expression in HLF. Overexpression of HA tagged USP11 (USP11-HA) enhanced TβRII lifespan. Co-immunostaining revealed that V5 tagged TβRII (TβRII-V5) and USP11-HA colocalized at plasma membrane and cytoplasm. TβRII ubiquitination was promoted by USP11 shRNA, while it was reduced by USP11-HA. Further, we investigated the role of USP11 in TGFβ1-mediated signaling, such as phosphorylation of SMAD2 and SMAD3. USP11-HA facilitated TGFβ1-induced phosphorylation of SMAD2 and SMAD3, which was attenuated in USP11 shRNA transfected HLF cells.
Conclusion This study indicates that USP11 contributes to the pathogenesis of pulmonary fibrosis by regulating targeting TβRII for its deubiquitination and stabilization.
This work was supported by the National Institutes of Health (R01HL091916 and R01HL112791 to Y.Z, R01GM115389 to J.Z.), American Heart Association 12SDG9050005 (J.Z.), American Lung Association Biomedical Research Grant RG350146 (J.Z.).
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