Desai LP, Zhou Y, Estrada AV, Ding Q, Cheng G, Collawn JF, Thannickal VJ

Hydrogen peroxide-inducible clone-5 (Hic-5) is a focal adhesion adaptor protein induced by the pro-fibrotic cytokine, transforming growth factor-β1 (TGF-β1). We have previously demonstrated that TGF-β1 induces myofibroblast differentiation and lung fibrosis by activation of the reactive oxygen species (ROS)-generating enzyme, NADPH oxidase 4 (Nox4). Here, we investigated a potential role for Hic-5 in regulating Nox4, myofibroblast differentiation and senescence. In normal human diploid fibroblasts, TGF-β1 induces Hic-5 expression in a delayed manner relative to induction of Nox4 and myofibroblast differentiation. Hic-5 silencing induced constitutive Nox4 expression and enhanced TGF-β1-inducible Nox4 levels. Induction of constitutive Nox4 protein in Hic-5 silenced cells was independent of transcription and translation, and controlled by the ubiquitin-proteasomal system (UPS). Hic-5 associates with the ubiquitin ligase, Cbl-c, and the ubiquitin-binding protein, heat shock protein 27 (HSP27). The interaction of these proteins is required for the ubiquitination of Nox4 and for maintaining low basal levels of this ROS-generating enzyme. Our model suggests that TGF-β1-induced Hic-5 functions as a negative feedback mechanism to limit myofibroblast differentiation and senescence by promoting UPS-mediated degradation of Nox4. Together, these studies indicate that endogenous Hic-5 suppresses senescence and pro-fibrotic activities of myofibroblasts by down-regulating Nox4 protein expression. Additionally, these are the first studies, to our knowledge, to demonstrate post-translational regulation of Nox4.

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