Inhibition of NAE-dependent protein hyper-NEDDylation in cystic cholangiocytes halts cystogenesis in experimental models of polycystic liver disease.
Pui Y Lee-LawPaula OlaizolaFrancisco J Caballero-CaminoLaura Izquierdo-SanchezPedro M RodriguesMaria J PerugorriaMikel AzkargortaFelix ElortzaMaria L Martinez-ChantarPatricia AspichuetaMarco MarzioniLuis BujandaJoost Paulus Hubertus DrenthJesus Maria BanalesPublished in: United European gastroenterology journal (2021)
The genes involved in the NEDDylation pathway were found overexpressed (mRNA) in polycystic human and rat liver tissue, as well as in cystic cholangiocytes in culture, compared to controls. Elevated levels of NEDDylated proteins were further confirmed in cystic cholangiocytes in vitro, which diminished under Pevonedistat incubation. Pevonedistat promoted apoptotic cell death and reduced proliferation in cystic cholangiocytes in vitro. Comparative proteomic profiling of NEDD8-immunoprecipitated proteins between normal and cystic cholangiocytes in culture reported candidate proteins involved in cystogenesis, mostly associated with protein biogenesis and quality control. All these data indicate that cystic cholangiocytes display increased protein NEDDylation, contributing to cell survival and proliferation, ultimately supporting hepatic cystogenesis. Targeting of protein hyper-NEDDylation in cystic cholangiocytes inhibits cystogenesis in experimental models, representing a novel therapeutic opportunity in PLD.