PMID- 22995918
OWN - NLM
STAT- MEDLINE
DCOM- 20130508
LR  - 20220310
IS  - 1554-8635 (Electronic)
IS  - 1554-8627 (Print)
IS  - 1554-8627 (Linking)
VI  - 8
IP  - 12
DP  - 2012 Dec
TI  - Impaired autophagy and delayed autophagic clearance of transforming growth factor 
      beta-induced protein (TGFBI) in granular corneal dystrophy type 2.
PG  - 1782-97
LID - 10.4161/auto.22067 [doi]
AB  - Granular corneal dystrophy type 2 (GCD2) is an autosomal dominant disease 
      characterized by a progressive age-dependent extracellular accumulation of 
      transforming growth factor beta-induced protein (TGFBI). Corneal fibroblasts from 
      GCD2 patients also have progressive degenerative features, but the mechanism 
      underlying this degeneration remains unknown. Here we observed that TGFBI was 
      degraded by autophagy, but not by the ubiquitin/proteasome-dependent pathway. We 
      also found that GCD2 homozygous corneal fibroblasts displayed a greater number of 
      fragmented mitochondria. Most notably, mutant TGFBI (mut-TGFBI) extensively 
      colocalized with microtubule-associated protein 1 light chain 3beta (MAP1LC3B, 
      hereafter referred to as LC3)-enriched cytosolic vesicles and CTSD in primary 
      cultured GCD2 corneal fibroblasts. Levels of LC3-II, a marker of autophagy 
      activation, were significantly increased in GCD2 corneal fibroblasts. 
      Nevertheless, levels of SQSTM1/p62 and of polyubiquitinated protein were also 
      significantly increased in GCD2 corneal fibroblasts compared with wild-type (WT) 
      cells. However, LC3-II levels did not differ significantly between WT and GCD2 
      cells, as assessed by the presence of bafilomycin A 1, the fusion blocker of 
      autophagosomes and lysosomes. Likewise, bafilomycin A 1 caused a similar change 
      in levels of SQSTM1. Thus, the increase in autophagosomes containing mut-TGFBI 
      may be due to inefficient fusion between autophagosomes and lysosomes. Rapamycin, 
      an autophagy activator, decreased mut-TGFBI, whereas inhibition of autophagy 
      increased active caspase-3, poly (ADP-ribose) polymerase 1 (PARP1) and reduced 
      the viability of GCD2 corneal fibroblasts compared with WT controls. These data 
      suggest that defective autophagy may play a critical role in the pathogenesis of 
      GCD2.
FAU - Choi, Seung-Il
AU  - Choi SI
AD  - Corneal Dystrophy Research Institute and Department of Ophthalmology, Yonsei 
      University College of Medicine, Seoul, Korea.
FAU - Kim, Bong-Yoon
AU  - Kim BY
FAU - Dadakhujaev, Shorafidinkhuja
AU  - Dadakhujaev S
FAU - Oh, Jun-Young
AU  - Oh JY
FAU - Kim, Tae-Im
AU  - Kim TI
FAU - Kim, Joo Young
AU  - Kim JY
FAU - Kim, Eung Kweon
AU  - Kim EK
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120920
PL  - United States
TA  - Autophagy
JT  - Autophagy
JID - 101265188
RN  - 0 (Biomarkers)
RN  - 0 (Extracellular Matrix Proteins)
RN  - 0 (Mutant Proteins)
RN  - 0 (Transforming Growth Factor beta)
RN  - 148710-76-3 (betaIG-H3 protein)
RN  - EC 3.4.22.- (Caspase 3)
RN  - W36ZG6FT64 (Sirolimus)
RN  - Corneal dystrophy Avellino type
SB  - IM
MH  - Adult
MH  - *Autophagy/drug effects
MH  - Biomarkers/metabolism
MH  - Caspase 3/metabolism
MH  - Cell Death/drug effects
MH  - Cell Survival/drug effects
MH  - Child
MH  - Cornea/drug effects/metabolism/pathology
MH  - Corneal Dystrophies, Hereditary/*metabolism/*pathology
MH  - Enzyme Activation/drug effects
MH  - Extracellular Matrix Proteins/*metabolism
MH  - Female
MH  - Fibroblasts/metabolism/pathology/ultrastructure
MH  - Humans
MH  - Intracellular Space/drug effects/metabolism
MH  - Kinetics
MH  - Lysosomes/drug effects/metabolism
MH  - Male
MH  - Membrane Fusion/drug effects
MH  - Middle Aged
MH  - Mutant Proteins/metabolism
MH  - Phagosomes/drug effects/metabolism
MH  - Proteolysis/drug effects
MH  - Sirolimus/pharmacology
MH  - Transforming Growth Factor beta/*metabolism
MH  - Young Adult
PMC - PMC3541288
EDAT- 2012/09/22 06:00
MHDA- 2013/05/09 06:00
PMCR- 2013/12/01
CRDT- 2012/09/22 06:00
PHST- 2012/09/22 06:00 [entrez]
PHST- 2012/09/22 06:00 [pubmed]
PHST- 2013/05/09 06:00 [medline]
PHST- 2013/12/01 00:00 [pmc-release]
AID - 22067 [pii]
AID - 2011AUTO0505R5 [pii]
AID - 10.4161/auto.22067 [doi]
PST - ppublish
SO  - Autophagy. 2012 Dec;8(12):1782-97. doi: 10.4161/auto.22067. Epub 2012 Sep 20.