0 863

Cited 16 times in

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

Authors
 Seung-il Choi  ;  Eunhee Lee  ;  Jang Bin Jeong  ;  Begum Akuzum  ;  Yong-Sun Maeng  ;  Tae-im Kim  ;  Eung Kweon Kim 
Citation
 BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, Vol.477(4) : 841-846, 2016 
Journal Title
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
ISSN
 0006-291X 
Issue Date
2016
MeSH
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*
Keywords
4-Phenylbutyric acid ; Corneal fibroblasts ; ER stress ; ERAD ; GCD2 ; TGFBIp ; UPR
Abstract
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.
Full Text
http://www.sciencedirect.com/science/article/pii/S0006291X16310737
DOI
10.1016/j.bbrc.2016.06.146
Appears in Collections:
1. College of Medicine (의과대학) > Research Institute (부설연구소) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Ophthalmology (안과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 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
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/151868
사서에게 알리기
  feedback

qrcode

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

Browse

Links