title: Autophagy and KRT8/keratin 8 protect degeneration of retinal pigment epithelium under oxidative stress.
abstract: Contribution of autophagy and regulation of related proteins to the degeneration of retinal pigment epithelium (RPE) in age-related macular degeneration (AMD) remain unknown. We report that upregulation of KRT8 (keratin 8) as well as its phosphorylation are accompanied with autophagy and attenuated with the inhibition of autophagy in RPE cells under oxidative stress. KRT8 appears to have a dual role in RPE pathophysiology. While increased expression of KRT8 following autophagy provides a cytoprotective role in RPE, phosphorylation of KRT8 induces pathologic epithelial-mesenchymal transition (EMT) of RPE cells under oxidative stress, which is mediated by MAPK1/ERK2 (mitogen-activated protein kinase 1) and MAPK3/ERK1. Inhibition of autophagy further promotes EMT, which can be reversed by inhibition of MAPK. Thus, regulated enhancement of autophagy with concurrent increased expression of KRT8 and the inhibition of KRT8 phosphorylation serve to inhibit oxidative stress-induced EMT of RPE cells as well as to prevent cell death, suggesting that pharmacological manipulation of KRT8 upregulation through autophagy with combined inhibition of the MAPK1/3 pathway may be attractive therapeutic strategies for the treatment of AMD.
authors.affiliation: a Department of Bioscience and Biotechnology , Konkuk University , Gwangjin-gu , Seoul , Korea.
authors.forename: Ahruem
authors.initials: A
authors.lastname: Baek
authors.affiliation: a Department of Bioscience and Biotechnology , Konkuk University , Gwangjin-gu , Seoul , Korea.
authors.forename: Soojin
authors.initials: S
authors.lastname: Yoon
authors.affiliation: b Department of Ophthalmology , Konkuk University School of Medicine , Gwangjin-gu , Seoul , Korea.
authors.forename: Jean
authors.initials: J
authors.lastname: Kim
authors.affiliation: a Department of Bioscience and Biotechnology , Konkuk University , Gwangjin-gu , Seoul , Korea.
authors.forename: Yu Mi
authors.initials: YM
authors.lastname: Baek
authors.affiliation: a Department of Bioscience and Biotechnology , Konkuk University , Gwangjin-gu , Seoul , Korea.
authors.forename: Hanna
authors.initials: H
authors.lastname: Park
authors.affiliation: b Department of Ophthalmology , Konkuk University School of Medicine , Gwangjin-gu , Seoul , Korea.
authors.forename: Daehan
authors.initials: D
authors.lastname: Lim
authors.affiliation: b Department of Ophthalmology , Konkuk University School of Medicine , Gwangjin-gu , Seoul , Korea.
authors.forename: Hyewon
authors.initials: H
authors.lastname: Chung
authors.affiliation: a Department of Bioscience and Biotechnology , Konkuk University , Gwangjin-gu , Seoul , Korea.
authors.forename: Dong-Eun
authors.initials: DE
authors.lastname: Kim
mesh_terms: D017209:Apoptosis; D000071182:Autophagosomes / Q000378:metabolism / Q000648:ultrastructure; D001343:Autophagy; D002460:Cell Line; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D019610:Cytoprotection; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D053533:Keratin-8 / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism / Q000648:ultrastructure; D008561:Membrane Fusion; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D008954:Models, Biological; D018384:Oxidative Stress; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D053533:Keratin-8; D013481:Superoxides; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1
keywords: KRT8 (keratin 8); age-related macular degeneration (AMD); apoptosis; autophagy; cell survival; epithelial-mesenchymal transition (EMT); mitogen-activated protein kinases 1 and 3 (MAPK1/3)