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

Choi, Seung Il; Lee, Eun-Hee; Jeong, Jang Bin; Akuzum, Begum; Maeng, Yong Sun; Kim, Tae Im; Kim, Eung Kweon

doi:10.1016/j.bbrc.2016.06.146

Cited by 14 publications

(25 citation statements)

References 32 publications

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“…Because CHOP is a significant mediator of ER stress‐related cell death in GDC2 cells, we investigated whether melatonin could inhibit GCD2 cell death by the suppression of CHOP. Melatonin treatment suppressed the levels of CHOP induced by tunicamycin treatment in both WT and GCD2 cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Previously, we demonstrated that, under ER stress conditions, TGFBIp could be degraded by the ERAD system . Therefore, to determine whether melatonin regulated TGFBIp levels through this system, cells were cotreated with or without melatonin and MG132 under ER stress.…”

Section: Resultsmentioning

confidence: 99%

“…TGFBIp is degraded by the ERAD system and mutant‐TGFBIp accumulates in GCD2 corneal cells. HRD1 and SEL1 are components of ERAD, which is a retrograde transport mechanism from the ER to the cytosol for eliminating misfolded proteins.…”

Section: Resultsmentioning

confidence: 99%

“…Melatonin has been reported to protect against the death of GCD2 corneal fibroblasts from oxidative stress and to enhance the degradation of mutant‐TGFBIp via activation of autophagy . Recently, we found that TGFBIp was degraded by the ERAD system under ER stress . In this study, we investigated whether melatonin could modulate activation of the UPR and prevent cell death caused by ER stress in GCD2 corneal fibroblasts, focusing on its regulating mechanism.…”

Section: Introductionmentioning

confidence: 98%

“…TGFBIp secretion via the ER/Golgi‐dependent secretory pathway is delayed in GCD2 corneal fibroblasts . Defective autophagy, accumulated mutant‐TGFBIp, delayed TGFBIp secretion, and enhanced ER stress are involved in the pathogenesis of GCD2.…”

Section: Introductionmentioning

confidence: 99%

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Melatonin reduces endoplasmic reticulum stress and corneal dystrophy‐associated TGFBIp through activation of endoplasmic reticulum‐associated protein degradation

Choi

Lee

Akuzum

et al. 2017

Journal of Pineal Research

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Endoplasmic reticulum (ER) stress is emerging as a factor for the pathogenesis of granular corneal dystrophy type 2 (GCD2). This study was designed to investigate the molecular mechanisms underlying the protective effects of melatonin on ER stress in GCD2. Our results showed that GCD2 corneal fibroblasts were more susceptible to ER stress-induced death than were wild-type cells. Melatonin significantly inhibited GCD2 corneal cell death, caspase-3 activation, and poly (ADP-ribose) polymerase 1 cleavage caused by the ER stress inducer, tunicamycin. Under ER stress, melatonin significantly suppressed the induction of immunoglobulin heavy-chain-binding protein (BiP) and activation of inositol-requiring enzyme 1α (IRE1α), and their downstream target, alternative splicing of X-box binding protein 1(XBP1). Notably, the reduction in BiP and IRE1α by melatonin was suppressed by the ubiquitin-proteasome inhibitor, MG132, but not by the autophagy inhibitor, bafilomycin A1, indicating involvement of the ER-associated protein degradation (ERAD) system. Melatonin treatment reduced the levels of transforming growth factor-β-induced protein (TGFBIp) significantly, and this reduction was suppressed by MG132. We also found reduced mRNA expression of the ERAD system components HRD1 and SEL1L, and a reduced level of SEL1L protein in GCD2 cells. Interestingly, melatonin treatments enhanced SEL1L levels and suppressed the inhibition of SEL1L N-glycosylation caused by tunicamycin. In conclusion, this study provides new insights into the mechanisms by which melatonin confers its protective actions during ER stress. The results also indicate that melatonin might have potential as a therapeutic agent for ER stress-related diseases including GCD2.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Melatonin reduces endoplasmic reticulum stress and corneal dystrophy‐associated TGFBIp through activation of endoplasmic reticulum‐associated protein degradation

Choi

Lee

Akuzum

et al. 2017

Journal of Pineal Research

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Prevalence of transforming growth factor β–induced gene corneal dystrophies in Chinese refractive surgery candidates

Song

Sun

Wang

et al. 2017

Journal of Cataract and Refractive Surgery

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Endoplasmic reticulum stress: molecular mechanism and therapeutic targets

Chen,

Shi,

et al. 2023

Sig Transduct Target Ther

171

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The endoplasmic reticulum (ER) functions as a quality-control organelle for protein homeostasis, or “proteostasis”. The protein quality control systems involve ER-associated degradation, protein chaperons, and autophagy. ER stress is activated when proteostasis is broken with an accumulation of misfolded and unfolded proteins in the ER. ER stress activates an adaptive unfolded protein response to restore proteostasis by initiating protein kinase R-like ER kinase, activating transcription factor 6, and inositol requiring enzyme 1. ER stress is multifaceted, and acts on aspects at the epigenetic level, including transcription and protein processing. Accumulated data indicates its key role in protein homeostasis and other diverse functions involved in various ocular diseases, such as glaucoma, diabetic retinopathy, age-related macular degeneration, retinitis pigmentosa, achromatopsia, cataracts, ocular tumors, ocular surface diseases, and myopia. This review summarizes the molecular mechanisms underlying the aforementioned ocular diseases from an ER stress perspective. Drugs (chemicals, neurotrophic factors, and nanoparticles), gene therapy, and stem cell therapy are used to treat ocular diseases by alleviating ER stress. We delineate the advancement of therapy targeting ER stress to provide new treatment strategies for ocular diseases.

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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

Cited by 14 publications

References 32 publications

Melatonin reduces endoplasmic reticulum stress and corneal dystrophy‐associated TGFBIp through activation of endoplasmic reticulum‐associated protein degradation

Melatonin reduces endoplasmic reticulum stress and corneal dystrophy‐associated TGFBIp through activation of endoplasmic reticulum‐associated protein degradation

Prevalence of transforming growth factor β–induced gene corneal dystrophies in Chinese refractive surgery candidates

Endoplasmic reticulum stress: molecular mechanism and therapeutic targets

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