The small heat-shock protein alphaB-crystallin is essential for the nuclear localization of Smad4: impact on pulmonary fibrosis.
Fiche publication
Date publication
mars 2014
Auteurs
Membres identifiés du Cancéropôle Est :
Dr GARRIDO Carmen, Dr BELLAYE Pierre-Simon, Pr BONNIAUD Philippe
Tous les auteurs :
Bellaye PS, Wettstein G, Burgy O, Besnard V, Joannes A, Colas J, Causse S, Marchal-Somme J, Fabre A, Crestani B, Kolb M, Gauldie J, Camus P, Garrido C, Bonniaud P
Lien Pubmed
Résumé
Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by the proliferation of myofibroblasts and the accumulation of extracellular matrix (ECM) in the lungs. TGF-beta1 is the major profibrotic cytokine involved in IPF and is responsible for myofibroblast proliferation and differentiation and ECM synthesis. alphaB-crystallin is constitutively expressed in the lungs and is inducible by stress, acts as a chaperone and is known to play a role in cell cytoskeleton architecture homeostasis. The role of alphaB-crystallin in fibrogenesis remains unknown. The principal signalling pathway involved in this process is the Smad-dependent pathway. We demonstrate here that alphaB-crystallin is strongly expressed in fibrotic lung tissue from IPF patients and in vivo rodent models of pulmonary fibrosis. We also show that alphaB-crystallin-deficient mice are protected from bleomycin-induced fibrosis. Similar protection from fibrosis was observed in alphaB-crystallin KO mice after transient adenoviral-mediated over-expression of IL-1beta or TGF-beta1. We show in vitro in primary epithelial cells and fibroblasts that alphaB-crystallin increases the nuclear localization of Smad4, thereby enhancing the TGF-beta1-Smad pathway and the consequent activation of TGF-beta1 downstream genes. alphaB-crystallin over-expression disrupts Smad4 mono-ubiquitination by interacting with its E3-ubiquitin ligase, TIF1gamma, thus limiting its nuclear export. Conversely, in the absence of alphaB-crystallin, TIF1gamma can freely interact with Smad4. Consequently, Smad4 mono-ubiquitination and nuclear export are favoured and thus TGF-beta1-Smad4 pro-fibrotic activity is inhibited. This study demonstrates that alphaB-crystallin may be a key target for the development of specific drugs in the treatment of IPF or other fibrotic diseases.
Référence
J Pathol. 2014 Mar;232(4):458-72