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Autophagy is induced by raptor degradation via the ubiquitin/proteasome system in granular corneal dystrophy type 2

 Seung-il Choi  ;  Yong-Sun Maeng  ;  Kyu Seo Kim  ;  Tae-im Kim  ;  Eung Kweon Kim 
 Biochemical and Biophysical Research Communications, Vol.450(4) : 1505-1511, 2014 
Journal Title
 Biochemical and Biophysical Research Communications 
Issue Date
Adaptor Proteins, Signal Transducing/metabolism* ; Autophagy* ; Corneal Dystrophies, Hereditary/enzymology ; Corneal Dystrophies, Hereditary/metabolism* ; Humans ; Proteasome Endopeptidase Complex/metabolism* ; Proteolysis ; Regulatory-Associated Protein of mTOR ; Ubiquitin/metabolism*
Autophagy ; Granular corneal dystrophy type 2 ; Raptor ; TGFBIp ; Ubiquitin/proteasome system ; mTOR
Granular corneal dystrophy type 2 (GCD2) is an autosomal dominant disorder that is caused by a point mutation in transforming growth factor-β-induced gene-h3 (TGFBI), which encodes transforming growth factor-β-induced protein (TGFBIp). Recently, we found that the autophagic clearance of mutant-TGFBIp is delayed in GCD2 corneal fibroblasts; however, any potential correlation between mutant-TGFBIp turnover and autophagy-lysosome pathway remains unknown. Here, we report that mutant-TGFBIp is accumulated and that autophagy, a key clearance pathway for mutant-TGFBIp, is induced in primary cultured GCD2 homozygous (HO) and wild-type (WT) corneal fibroblasts that express exogenously introduced mutant-TGFBIp. Mutant-TGFBI colocalized with LC3-enriched cytosolic vesicles and cathepsin D in primary cultured GCD2 corneal fibroblasts. We also observed reduced levels of raptor (regulatory-associated protein of the mammalian target of rapamycin [mTOR]) in GCD2 corneal fibroblasts and WT corneal fibroblasts expressing mutant-TGFBIp. Strikingly, treatment with MG132, a ubiquitin/proteasome system inhibitor, significantly increased the levels of both total and ubiquitinated raptor in GCD2 corneal fibroblasts. The levels of the autophagy marker LC3-II were also increased in WT corneal fibroblasts that were treated with shRNA against raptor. However, mutant-TGFBIp accumulated in autophagosomes or/and lysosomes in spite of the significant activation of basal autophagy in GCD2 corneal fibroblasts. These results suggest that an insufficient autophagy-lysosome pathway might be responsible for the intracellular accumulation of mutant-TGFBIp during the pathogenesis of GCD2
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Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Ophthalmology (안과학교실) > 1. Journal Papers
5. Research Institutes (연구소) > Corneal Dystrophy Research Institute (각막이상증연구소) > 1. Journal Papers
Yonsei Authors
Kim, Eung Kweon(김응권) ORCID logo https://orcid.org/0000-0002-1453-8042
Kim, Tae Im(김태임) ORCID logo https://orcid.org/0000-0001-6414-3842
Maeng, Yong Sun(맹용선) ORCID logo https://orcid.org/0000-0003-1694-8405
Choi, Seung Il(최승일) ORCID logo https://orcid.org/0000-0001-7168-8795
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