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ID: 118: UBIQUITIN E3 LIGASE FIEL1 REGUALTES TGFBETA SIGNALING IN LUNG FIBROBLAST
  1. JY Zhao,
  2. B Chen
  1. Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Abstract

Tumor growth factor β (TGFb) signaling plays a key role in the pathogenesis of tissue fibrosis, specifically Idiopathic Pulmonary Fibrosis (IPF). IPF is the deadliest of interstitial lung diseases with a median survival of merely three years. Currently IPF affects more than 35,000 patients each year, but despite extensive research, there is still no effective treatment. Thus, the discovery of new models that regulate TGFb signaling and reveal “authentic” drug targets could serve as a springboard for the introduction of a new generation of anti-fibrotic agents to be used in the clinical arena. There is a fundamental, unmet scientific and clinical need to discover new mechanistic models that control overactive TGFb signaling and, when left unchecked, can produce severe tissue fibrosis.

PIAS4 is a pivotal protein in controlling TGFβ effects. Here we discovered a new protein isoform encoded by KIAA0317, termed FIEL1 (Fibrosis Inducing E3 Ligase 1), that potently stimulates TGFβ signaling pathway through the site-specific ubiquitination and destabilization of PIAS4. FIEL1 protein is highly expressed in lung tissues from patients with Idiopathic Pulmonary Fibrosis (IPF), whereas PIAS4 protein levels are significantly reduced. FIEL1 overexpression significantly activates TGFβ signaling. Further, we developed a novel small molecule inhibitor towards FIEL1 that is highly effective in ameliorating TGFβ signaling. This study provides a basis for IPF therapeutic intervention by modulating PIAS4 protein abundance.

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