Inactivation of nuclear histone deacetylases by EP300 disrupts the MiCEE complex in idiopathic pulmonary fibrosis. Rubio Karla,Singh Indrabahadur,Dobersch Stephanie,Sarvari Pouya,Günther Stefan,Cordero Julio,Mehta Aditi,Wujak Lukasz,Cabrera-Fuentes Hector,Chao Cho-Ming,Braubach Peter,Bellusci Saverio,Seeger Werner,Günther Andreas,Preissner Klaus T,Wygrecka Malgorzata,Savai Rajkumar,Papy-Garcia Dulce,Dobreva Gergana,Heikenwalder Mathias,Savai-Pullamsetti Soni,Braun Thomas,Barreto Guillermo Nature communications Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and highly lethal lung disease with unknown etiology and poor prognosis. IPF patients die within 2 years after diagnosis mostly due to respiratory failure. Current treatments against IPF aim to ameliorate patient symptoms and to delay disease progression. Unfortunately, therapies targeting the causes of or reverting IPF have not yet been developed. Here we show that reduced levels of miRNA lethal 7d (MIRLET7D) in IPF compromise epigenetic gene silencing mediated by the ribonucleoprotein complex MiCEE. In addition, we find that hyperactive EP300 reduces nuclear HDAC activity and interferes with MiCEE function in IPF. Remarkably, EP300 inhibition reduces fibrotic hallmarks of in vitro (patient-derived primary fibroblast), in vivo (bleomycin mouse model), and ex vivo (precision-cut lung slices, PCLS) IPF models. Our work provides the molecular basis for therapies against IPF using EP300 inhibition. 10.1038/s41467-019-10066-7

Conditional deletion of Nedd4-2 in lung epithelial cells causes progressive pulmonary fibrosis in adult mice. Duerr Julia,Leitz Dominik H W,Szczygiel Magdalena,Dvornikov Dmytro,Fraumann Simon G,Kreutz Clemens,Zadora Piotr K,Seyhan Agircan Ayça,Konietzke Philip,Engelmann Theresa A,Hegermann Jan,Mulugeta Surafel,Kawabe Hiroshi,Knudsen Lars,Ochs Matthias,Rotin Daniela,Muley Thomas,Kreuter Michael,Herth Felix J F,Wielpütz Mark O,Beers Michael F,Klingmüller Ursula,Mall Marcus A Nature communications Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease characterized by patchy scarring of the distal lung with limited therapeutic options and poor prognosis. Here, we show that conditional deletion of the ubiquitin ligase Nedd4-2 (Nedd4l) in lung epithelial cells in adult mice produces chronic lung disease sharing key features with IPF including progressive fibrosis and bronchiolization with increased expression of Muc5b in peripheral airways, honeycombing and characteristic alterations in the lung proteome. NEDD4-2 is implicated in the regulation of the epithelial Na channel critical for proper airway surface hydration and mucus clearance and the regulation of TGFβ signaling, which promotes fibrotic remodeling. Our data support a role of mucociliary dysfunction and aberrant epithelial pro-fibrotic response in the multifactorial disease pathogenesis. Further, treatment with the anti-fibrotic drug pirfenidone reduced pulmonary fibrosis in this model. This model may therefore aid studies of the pathogenesis and therapy of IPF. 10.1038/s41467-020-15743-6