The small heat-shock protein αB-crystallin is essential for the nuclear localization of Smad4: impact on pulmonary fibrosis

被引:55
作者
Bellaye, Pierre-Simon [1 ,2 ]
Wettstein, Guillaume [1 ,2 ]
Burgy, Olivier [1 ,2 ]
Besnard, Valerie [3 ]
Joannes, Audrey [3 ]
Colas, Julien [1 ,2 ]
Causse, Sebastien [1 ,2 ]
Marchal-Somme, Joelle [3 ]
Fabre, Aurelie [4 ]
Crestani, Bruno [3 ,5 ,6 ]
Kolb, Martin [7 ]
Gauldie, Jack [7 ]
Camus, Philippe [1 ,2 ,8 ]
Garrido, Carmen [1 ,2 ]
Bonniaud, Philippe [1 ,2 ,8 ]
机构
[1] INSERM, U866, Equipe Labellisee Ligue Canc, Dijon, France
[2] Univ Burgundy, Fac Med & Pharm, Dijon, France
[3] INSERM, U700, Paris, France
[4] St Vincents Univ Hosp, Dublin 4, Ireland
[5] Univ Paris Diderot, PRES Sorbonne Paris Cite, Paris, France
[6] Hop Bichat Claude Bernard, Paris APHP, Serv Pneumol A, Fac Med Bichat, F-75877 Paris, France
[7] McMaster Univ, Ctr Gene Therapeut, Hamilton, ON, Canada
[8] CHU, Serv Pneumol, Dijon, France
关键词
GROWTH-FACTOR-BETA; TGF-BETA; INFLAMMATORY MECHANISMS; INCREASED EXPRESSION; EPITHELIAL-CELLS; MINOR COMPONENT; PATHOGENESIS; GENE; RAT; EMT;
D O I
10.1002/path.4314
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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. Copyright © 2013 Pathological Society of Great Britain and Ireland. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
引用
收藏
页码:458 / 472
页数:15
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