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4-Phenylbutyric acid reduces mutant-TGFBIp levels and ER stress through activation of ERAD pathway in corneal fibroblasts of granular corneal dystrophy type 2

 Seung-il Choi  ;  Eunhee Lee  ;  Jang Bin Jeong  ;  Begum Akuzum  ;  Yong-Sun Maeng  ;  Tae-im Kim  ;  Eung Kweon Kim 
 Biochemical and Biophysical Research Communications, Vol.477(4) : 841-846, 2016 
Journal Title
 Biochemical and Biophysical Research Communications 
Issue Date
Apoptosis/drug effects ; Cells, Cultured ; Cornea/drug effects ; Cornea/metabolism ; Cornea/physiopathology* ; Corneal Dystrophies, Hereditary/drug therapy ; Corneal Dystrophies, Hereditary/pathology ; Corneal Dystrophies, Hereditary/physiopathology* ; Dose-Response Relationship, Drug ; Down-Regulation/drug effects ; Endoplasmic Reticulum Stress/drug effects* ; Endoplasmic Reticulum-Associated Degradation/drug effects* ; Extracellular Matrix Proteins/genetics ; Extracellular Matrix Proteins/metabolism* ; Fibroblasts/drug effects ; Fibroblasts/metabolism ; Fibroblasts/pathology ; Humans ; Mutation/drug effects ; Mutation/genetics ; Phenylbutyrates/administration & dosage* ; Transforming Growth Factor beta/genetics ; Transforming Growth Factor beta/metabolism*
4-Phenylbutyric acid ; Corneal fibroblasts ; ER stress ; ERAD ; GCD2 ; TGFBIp ; UPR
Granular corneal dystrophy type 2 (GCD2) is caused by a point mutation (R124H) in the transforming growth factor β-induced (TGFBI) gene. In GCD2 corneal fibroblasts, secretion of the accumulated mutant TGFBI-encoded protein (TGFBIp) is delayed via the endoplasmic reticulum (ER)/Golgi-dependent secretory pathway. However, ER stress as the pathogenic mechanism underlying GCD2 has not been fully characterized. The aim of this study was to confirm whether ER stress is linked to GCD2 pathogenesis and whether the chemical chaperone, 4-phenylbutyric acid (4-PBA), could be exploited as a therapy for GCD2. We found that the ER chaperone binding immunoglobulin protein (BiP) and the protein disulfide isomerase (PDI) were elevated in GCD2. Western bolt analysis also showed a significant increase in both the protein levels and the phosphorylation of the key ER stress kinases, inositol-requiring enzyme 1α (IRE1α) and double stranded RNA activated protein kinase (PKR)-like ER kinase, as well as in levels of their downstream targets, X box-binding protein 1 (XBP1) and activating transcription factor 4, respectively, in GCD2 corneal fibroblasts. GCD2 cells were found to be more susceptible to ER stress-induced cell death than were wild-type corneal fibroblasts. Treatment with 4-PBA considerably reduced the levels of BiP, IRE1α, and XBP1 in GCD2 cells; notably, 4-PBA treatment significantly reduced the levels of TGFBIp without change in TGFBI mRNA levels. In addition, TGFBIp levels were significantly reduced under ER stress and this reduction was considerably suppressed by the ubiquitin proteasome inhibitor MG132, indicating TGFBIp degradation via the ER-associated degradation pathway. Treatment with 4-PBA not only protected against the GCD2 cell death induced by ER stress but also significantly suppressed the MG132-mediated increase in TGFBIp levels under ER stress. Together, these results suggest that ER stress might comprise an important factor in GCD2 pathophysiology and that the effects of 4-PBA treatment might have important implications for the development of GCD2 therapeutics.
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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
김응권(Kim, Eung Kweon) ORCID logo https://orcid.org/0000-0002-1453-8042
김태임(Kim, Tae Im) ORCID logo https://orcid.org/0000-0001-6414-3842
맹용선(Maeng, Yong Sun) ORCID logo https://orcid.org/0000-0003-1694-8405
최승일(Choi, Seung Il) ORCID logo https://orcid.org/0000-0001-7168-8795
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