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Impaired autophagy and delayed autophagic clearance of transforming growth factor β-induced protein (TGFBI) in granular corneal dystrophy type 2

 Seung-Il Choi  ;  Bong-Yoon Kim  ;  Shorafidinkhuja Dadakhujaev  ;  Jun-Young Oh  ;  Tae-Im Kim  ;  Joo Young Kim  ;  Eung Kweon Kim 
 AUTOPHAGY, Vol.8(12) : 1782-1797, 2012 
Journal Title
Issue Date
Adult ; Autophagy*/drug effects ; Biomarkers/metabolism ; Caspase 3/metabolism ; Cell Death/drug effects ; Cell Survival/drug effects ; Child ; Cornea/drug effects ; Cornea/metabolism ; Cornea/pathology ; Corneal Dystrophies, Hereditary/metabolism* ; Corneal Dystrophies, Hereditary/pathology* ; Enzyme Activation/drug effects ; Extracellular Matrix Proteins/metabolism* ; Female ; Fibroblasts/metabolism ; Fibroblasts/pathology ; Fibroblasts/ultrastructure ; Humans ; Intracellular Space/drug effects ; Intracellular Space/metabolism ; Kinetics ; Lysosomes/drug effects ; Lysosomes/metabolism ; Male ; Membrane Fusion/drug effects ; Middle Aged ; Mutant Proteins/metabolism ; Phagosomes/drug effects ; Phagosomes/metabolism ; Proteolysis/drug effects ; Sirolimus/pharmacology ; Transforming Growth Factor beta/metabolism* ; Young Adult
LC3/MAP1LC3B ; SQSTM1/p62 ; TGFBI ; defective autophagy ; rapamycin ; ubiquitination
Granular corneal dystrophy type 2 (GCD2) is an autosomal dominant disease characterized by a progressive age-dependent extracellular accumulation of transforming growth factor β-induced protein (TGFBI). Corneal fibroblasts from GCD2 patients also have progressive degenerative features, but the mechanism underlying this degeneration remains unknown. Here we observed that TGFBI was degraded by autophagy, but not by the ubiquitin/proteasome-dependent pathway. We also found that GCD2 homozygous corneal fibroblasts displayed a greater number of fragmented mitochondria. Most notably, mutant TGFBI (mut-TGFBI) extensively colocalized with microtubule-associated protein 1 light chain 3β (MAP1LC3B, hereafter referred to as LC3)-enriched cytosolic vesicles and CTSD in primary cultured GCD2 corneal fibroblasts. Levels of LC3-II, a marker of autophagy activation, were significantly increased in GCD2 corneal fibroblasts. Nevertheless, levels of SQSTM1/p62 and of polyubiquitinated protein were also significantly increased in GCD2 corneal fibroblasts compared with wild-type (WT) cells. However, LC3-II levels did not differ significantly between WT and GCD2 cells, as assessed by the presence of bafilomycin A 1, the fusion blocker of autophagosomes and lysosomes. Likewise, bafilomycin A 1 caused a similar change in levels of SQSTM1. Thus, the increase in autophagosomes containing mut-TGFBI may be due to inefficient fusion between autophagosomes and lysosomes. Rapamycin, an autophagy activator, decreased mut-TGFBI, whereas inhibition of autophagy increased active caspase-3, poly (ADP-ribose) polymerase 1 (PARP1) and reduced the viability of GCD2 corneal fibroblasts compared with WT controls. These data suggest that defective autophagy may play a critical role in the pathogenesis of GCD2.
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1. College of Medicine (의과대학) > Research Institute (부설연구소) > 1. Journal Papers
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Ophthalmology (안과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Bong Yoon(김봉윤)
Kim, Eung Kweon(김응권) ORCID logo https://orcid.org/0000-0002-1453-8042
Kim, Joo Young(김주영) ORCID logo https://orcid.org/0000-0003-2623-1491
Kim, Tae-Im(김태임) ORCID logo https://orcid.org/0000-0001-6414-3842
Dadakhujaev, Shorafidinkhuja(다다후자예프)
Oh, Jun Young(오준영)
Choi, Seung Il(최승일) ORCID logo https://orcid.org/0000-0001-7168-8795
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