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

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25 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1505-1511
Number of pages7
JournalBiochemical and Biophysical Research Communications
Issue number4
Publication statusPublished - 2014 Aug 8

Bibliographical note

Funding Information:
The authors thank Jun-Young Oh, and Jun-Yup Jin for their technical assistance. This research was supported by a Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF 2013R1A1A2012958), and by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MEST) (2011-0028699).

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology


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