ZAC-1 regulates TGFβ-dependent fibroblast activation in fibrotic diseases by modulation of AP-1 signaling

• Applicant: Professor Dr. Jörg Hans Wilhelm Distler
• Subject Area: Rheumatology
• Term: from 2020 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 437567911

excessive deposition of extracellular matrix with perturbation of the physiological tissue architecture and impairment the physiological function of the affected organs. Fibrotic tissue remodeling imposes a major burden on modern societies and has been estimated to contribute to up to 45% of deaths in the developed world. SSc and other fibrotic diseases are characterized by an uncontrolled, persistent activation of fibroblasts. These myofibroblasts continue to release excessive amounts of extracellular matrix, which leads to excessive accumulation of extracellular matrix and progressive tissue fibrosis. Although several mediators of fibroblast activation such as transforming growth factor-β (TGFβ) have been identified, it remains poorly understood, how they drive the chronic activation of fibroblasts and the progressive tissue remodelling. Our preliminary results provide first evidence that the zinc finger transcription factor Zac-1 orchestrates a positive feedback loop that amplifies TGFβ signaling in fibrosis. TGFβ upregulates the expression of Zac-1 in SSc. Zac-1 in turn enhances the stimulatory effects of TGFβ on fibroblasts, promotes fibroblast-to-myofibroblast transition and collagen release and exacerbates experimental fibrosis. Knockdown of Zac-1 ameliorates the profibrotic effects of TGFβ in vitro and in vivo. Mechanistically, the Zac-1 seems to amplify the profibrotic effects of TGFβ by promoting AP-1 activation. To further characterize the role of Zac-1 in the pathogenesis of fibrotic diseases, we now aim to: 1.) Correlate the expression levels and patterns of Zac-1 with clinical characteristics of patients with SSc and other fibrotic diseases, 2.) decipher the regulatory effects of Zac-1 on fibroblasts in more detail, 3.) analyse the profibrotic of Zac-1 in additional murine models resembling different subgroups and stages of SSc and 4.) unravel the functional role and the regulation of AP-1 signaling in the Zac-1 amplification loop. These data may establish Zac-1 as a target for antifibrotic therapies in SSc.

• DFG Programme: Research Grants