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TGF\u2010<jats:italic>\u03b2<\/jats:italic>1 is the major profibrotic cytokine involved in IPF and is responsible for myofibroblast proliferation and differentiation and ECM synthesis. <jats:italic>\u03b1<\/jats:italic>B\u2010crystallin 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 <jats:italic>\u03b1<\/jats:italic>B\u2010crystallin in fibrogenesis remains unknown. The principal signalling pathway involved in this process is the Smad\u2010dependent pathway. We demonstrate here that <jats:italic>\u03b1<\/jats:italic>B\u2010crystallin is strongly expressed in fibrotic lung tissue from IPF patients and <jats:italic>in vivo<\/jats:italic> rodent models of pulmonary fibrosis. We also show that <jats:italic>\u03b1<\/jats:italic>B\u2010crystallin\u2010deficient mice are protected from bleomycin\u2010induced fibrosis. Similar protection from fibrosis was observed in <jats:italic>\u03b1<\/jats:italic>B\u2010crystallin KO mice after transient adenoviral\u2010mediated over\u2010expression of IL\u20101<jats:italic>\u03b2<\/jats:italic> or TGF\u2010<jats:italic>\u03b2<\/jats:italic>1. We show <jats:italic>in vitro<\/jats:italic> in primary epithelial cells and fibroblasts that <jats:italic>\u03b1<\/jats:italic>B\u2010crystallin increases the nuclear localization of Smad4, thereby enhancing the TGF\u2010<jats:italic>\u03b2<\/jats:italic>1\u2013Smad pathway and the consequent activation of TGF\u2010<jats:italic>\u03b2<\/jats:italic>1 downstream genes. <jats:italic>\u03b1<\/jats:italic>B\u2010crystallin over\u2010expression disrupts Smad4 mono\u2010ubiquitination by interacting with its E3\u2013ubiquitin ligase, TIF1<jats:italic>\u03b3<\/jats:italic>, thus limiting its nuclear export. Conversely, in the absence of <jats:italic>\u03b1<\/jats:italic>B\u2010crystallin, TIF1<jats:italic>\u03b3<\/jats:italic> can freely interact with Smad4. Consequently, Smad4 mono\u2010ubiquitination and nuclear export are favoured and thus TGF\u2010<jats:italic>\u03b2<\/jats:italic>1\u2013Smad4 pro\u2010fibrotic activity is inhibited. This study demonstrates that <jats:italic>\u03b1<\/jats:italic>B\u2010crystallin may be a key target for the development of specific drugs in the treatment of IPF or other fibrotic diseases. Copyright \u00a9 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.<\/jats:bold><\/jats:p>","DOI":"10.1002\/path.4314","type":"journal-article","created":{"date-parts":[[2013,12,4]],"date-time":"2013-12-04T13:41:51Z","timestamp":1386164511000},"page":"458-472","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":62,"title":["The small heat\u2010shock protein <i>\u03b1<\/i><scp>B<\/scp>\u2010crystallin is essential for the nuclear localization of Smad4: impact on pulmonary fibrosis"],"prefix":"10.1002","volume":"232","author":[{"given":"Pierre\u2010Simon","family":"Bellaye","sequence":"first","affiliation":[{"name":"INSERM U866 \u00c9quipe Labellis\u00e9e Ligue Contre le Cancer Dijon France"},{"name":"Faculty of Medicine and Pharmacy University of Burgundy Dijon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillaume","family":"Wettstein","sequence":"additional","affiliation":[{"name":"INSERM U866 \u00c9quipe Labellis\u00e9e Ligue 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