title: αB-Crystallin Regulates Subretinal Fibrosis by Modulation of Epithelial-Mesenchymal Transition.
abstract: Subretinal fibrosis is an end stage of neovascular age-related macular degeneration, characterized by fibrous membrane formation after choroidal neovascularization. An initial step of the pathogenesis is an epithelial-mesenchymal transition (EMT) of retinal pigment epithelium cells. αB-crystallin plays multiple roles in age-related macular degeneration, including cytoprotection and angiogenesis. However, the role of αB-crystallin in subretinal EMT and fibrosis is unknown. Herein, we showed attenuation of subretinal fibrosis after regression of laser-induced choroidal neovascularization and a decrease in mesenchymal retinal pigment epithelium cells in αB-crystallin knockout mice compared with wild-type mice. αB-crystallin was prominently expressed in subretinal fibrotic lesions in mice. In vitro, overexpression of αB-crystallin induced EMT, whereas suppression of αB-crystallin induced a mesenchymal-epithelial transition. Transforming growth factor-β2-induced EMT was further enhanced by overexpression of αB-crystallin but was inhibited by suppression of αB-crystallin. Silencing of αB-crystallin inhibited multiple fibrotic processes, including cell proliferation, migration, and fibronectin production. Bone morphogenetic protein 4 up-regulated αB-crystallin, and its EMT induction was inhibited by knockdown of αB-crystallin. Furthermore, inhibition of αB-crystallin enhanced monotetraubiquitination of SMAD4, which can impair its nuclear localization. Overexpression of αB-crystallin enhanced nuclear translocation and accumulation of SMAD4 and SMAD5. Thus, αB-crystallin is an important regulator of EMT, acting as a molecular chaperone for SMAD4 and as its potential therapeutic target for preventing subretinal fibrosis development in neovascular age-related macular degeneration.
authors.affiliation: Arnold and Mabel Beckman Macular Research Center, Doheny Eye Institute, Los Angeles, California; Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, California.
authors.forename: Keijiro
authors.initials: K
authors.lastname: Ishikawa
authors.affiliation: Arnold and Mabel Beckman Macular Research Center, Doheny Eye Institute, Los Angeles, California.
authors.forename: Parameswaran G
authors.initials: PG
authors.lastname: Sreekumar
authors.affiliation: Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, California.
authors.forename: Christine
authors.initials: C
authors.lastname: Spee
authors.affiliation: Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, California.
authors.forename: Hossein
authors.initials: H
authors.lastname: Nazari
authors.affiliation: Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California.
authors.forename: Danhong
authors.initials: D
authors.lastname: Zhu
authors.affiliation: Arnold and Mabel Beckman Macular Research Center, Doheny Eye Institute, Los Angeles, California.
authors.forename: Ram
authors.initials: R
authors.lastname: Kannan
authors.affiliation: Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, California; Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California. Electronic address: dhinton@usc.edu.
authors.forename: David R
authors.initials: DR
authors.lastname: Hinton
mesh_terms: D000818:Animals; D020256:Choroidal Neovascularization / Q000235:genetics / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism*; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics / Q000473:pathology*; D008297:Male; D018345:Mice, Knockout; D055213:Retinal Pigment Epithelium / Q000378:metabolism* / Q000473:pathology; D038203:alpha-Crystallin B Chain / Q000235:genetics / Q000378:metabolism*
chemical_list: D005353:Fibronectins; D038203:alpha-Crystallin B Chain