The small heat‐shock protein αB‐crystallin is essential for the nuclear localization of Smad4: impact on pulmonary fibrosis. Issue 4 (March 2014)

• Record Type: Journal Article
• Authors: Bellaye, Pierre‐Simon; Wettstein, Guillaume; Burgy, Olivier; Besnard, Valérie; Joannes, Audrey; Colas, Julien; Causse, Sébastien; Marchal‐Somme, Joëlle; Fabre, Aurélie; Crestani, Bruno; Kolb, Martin; Gauldie, Jack; Camus, Philippe; Garrido, Carmen; Bonniaud, Philippe
• Is Part Of: Journal of pathology. Volume 232:Issue 4(2014)
• Page Start: 458
• Page End: 472
• Publication Date: 2014-03
• Subjects: Pathology -- Periodicals; 616.07
• DOI: 10.1002/path.4314
• Languages: English
• ISSNs: 0022-3417

Abstract

<abstract abstract-type="main" id="path4314-abs-0001"> <title>Abstract</title> <p id="path4314-para-0001"> <bold>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‐<italic>β</italic>1 is the major profibrotic cytokine involved in IPF and is responsible for myofibroblast proliferation and differentiation and ECM synthesis. <italic>α</italic>B‐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 <italic>α</italic>B‐crystallin in fibrogenesis remains unknown. The principal signalling pathway involved in this process is the Smad‐dependent pathway. We demonstrate here that <italic>α</italic>B‐crystallin is strongly expressed in fibrotic lung tissue from IPF patients and <italic>in vivo</italic> rodent models of pulmonary fibrosis. We also show that <italic>α</italic>B‐crystallin‐deficient mice are protected from bleomycin‐induced fibrosis. Similar protection from fibrosis was observed in <italic>α</italic>B‐crystallin KO mice after transient adenoviral‐mediated over‐expression of IL‐1<italic>β</italic> or TGF‐<italic>β</italic>1. We show <italic>in vitro</italic> in primary epithelial cells and fibroblasts that <italic>α</italic>B‐crystallin increases the nuclear localization of Smad4, thereby enhancing the TGF‐<italic>β</italic>1–Smad pathway and the consequent activation of TGF‐<italic>β</italic>1 downstream genes. <italic>α</italic>B‐crystallin over‐expression disrupts Smad4 mono‐ubiquitination by interacting with its E3–ubiquitin ligase, TIF1<italic>γ</italic>, thus limiting its nuclear export. Conversely, in the absence of <italic>α</italic>B‐crystallin, TIF1<italic>γ</italic> can freely interact with Smad4. Consequently, Smad4 mono‐ubiquitination and nuclear export are favoured and thus TGF‐<italic>β</italic>1–Smad4 pro‐fibrotic activity is inhibited. This study demonstrates that <italic>α</italic>B‐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. Published by John Wiley & Sons, Ltd.</bold> </p> </abstract>