title: The small heat-shock protein αB-crystallin is essential for the nuclear localization of Smad4: impact on pulmonary fibrosis.
abstract: 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-β1 is the major profibrotic cytokine involved in IPF and is responsible for myofibroblast proliferation and differentiation and ECM synthesis. αB-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 αB-crystallin in fibrogenesis remains unknown. The principal signalling pathway involved in this process is the Smad-dependent pathway. We demonstrate here that αB-crystallin is strongly expressed in fibrotic lung tissue from IPF patients and in vivo rodent models of pulmonary fibrosis. We also show that αB-crystallin-deficient mice are protected from bleomycin-induced fibrosis. Similar protection from fibrosis was observed in αB-crystallin KO mice after transient adenoviral-mediated over-expression of IL-1β or TGF-β1. We show in vitro in primary epithelial cells and fibroblasts that αB-crystallin increases the nuclear localization of Smad4, thereby enhancing the TGF-β1-Smad pathway and the consequent activation of TGF-β1 downstream genes. αB-crystallin over-expression disrupts Smad4 mono-ubiquitination by interacting with its E3-ubiquitin ligase, TIF1γ, thus limiting its nuclear export. Conversely, in the absence of αB-crystallin, TIF1γ can freely interact with Smad4. Consequently, Smad4 mono-ubiquitination and nuclear export are favoured and thus TGF-β1-Smad4 pro-fibrotic activity is inhibited. This study demonstrates that αB-crystallin may be a key target for the development of specific drugs in the treatment of IPF or other fibrotic diseases.
authors.affiliation: INSERM U866 Équipe Labellisée Ligue Contre le Cancer, Dijon, France; Faculty of Medicine and Pharmacy, University of Burgundy, Dijon, France.
authors.forename: Pierre-Simon
authors.initials: PS
authors.lastname: Bellaye
authors.forename: Guillaume
authors.initials: G
authors.lastname: Wettstein
authors.forename: Olivier
authors.initials: O
authors.lastname: Burgy
authors.forename: Valérie
authors.initials: V
authors.lastname: Besnard
authors.forename: Audrey
authors.initials: A
authors.lastname: Joannes
authors.forename: Julien
authors.initials: J
authors.lastname: Colas
authors.forename: Sébastien
authors.initials: S
authors.lastname: Causse
authors.forename: Joëlle
authors.initials: J
authors.lastname: Marchal-Somme
authors.forename: Aurélie
authors.initials: A
authors.lastname: Fabre
authors.forename: Bruno
authors.initials: B
authors.lastname: Crestani
authors.forename: Martin
authors.initials: M
authors.lastname: Kolb
authors.forename: Jack
authors.initials: J
authors.lastname: Gauldie
authors.forename: Philippe
authors.initials: P
authors.lastname: Camus
authors.forename: Carmen
authors.initials: C
authors.lastname: Garrido
authors.forename: Philippe
authors.initials: P
authors.lastname: Bonniaud
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D001761:Bleomycin; D002467:Cell Nucleus / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D051901:Smad4 Protein / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination; D038203:alpha-Crystallin B Chain / Q000235:genetics / Q000378:metabolism*
chemical_list: C059215:CRYAB protein, human; C525420:Cryab protein, mouse; D053583:Interleukin-1beta; C497796:SMAD4 protein, human; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; C490811:Smad4 protein, rat; C511956:TRIM33 protein, human; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D038203:alpha-Crystallin B Chain; D001761:Bleomycin; D003094:Collagen; D044767:Ubiquitin-Protein Ligases
keywords: TGF-β1; fibrogenesis; heat-shock proteins; inflammation