PMID- 27604640
OWN - NLM
STAT- MEDLINE
DCOM- 20180604
LR  - 20220331
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 6
DP  - 2016 Sep 8
TI  - Ubiquitin carboxyl-terminal hydrolase-L5 promotes TGFbeta-1 signaling by 
      de-ubiquitinating and stabilizing Smad2/Smad3 in pulmonary fibrosis.
PG  - 33116
LID - 10.1038/srep33116 [doi]
LID - 33116
AB  - Transforming growth factor beta-1 (TGFbeta-1)-induced phosphorylation of transcription 
      factors Smad2 and Smad3 plays a crucial role in the pathogenesis of idiopathic 
      pulmonary fibrosis (IPF). However, the molecular regulation of Smad2/Smad3 
      proteins stability remains a mystery. Here, we show that ubiquitin 
      carboxyl-terminal hydrolase-L5 (UCHL5 or UCH37) de-ubiquitinates both Smad2 and 
      Smad3, up-regulates their stability, and promotes TGFbeta-1-induced expression of 
      profibrotic proteins, such as fibronectin (FN) and alpha-smooth muscle actin (alpha-SMA). 
      Inhibition or down-regulation of UCHL5 reduced Smad2/Smad3 levels and 
      TGFbeta-1-induced the expression of FN and alpha-SMA in human lung fibroblast. We 
      demonstrate that Smad2 and Smad3 ubiquitination was diminished by over-expression 
      of UCHL5, while it was enhanced by inhibition or down-regulation of UCHL5. UCHL5 
      is highly expressed in IPF lungs. UCHL5, Smad2, and Smad3 levels were increased 
      in bleomycin-injured lungs. Administration of UCHL5 inhibitor, b-AP15, reduced 
      the expression of FN, type I collagen, Smad2/Smad3, and the deposition of 
      collagen in lung tissues in a bleomycin-induced model of pulmonary fibrosis. Our 
      studies provide a molecular mechanism by which UCHL5 mitigates TGFbeta-1 signaling 
      by stabilizing Smad2/Smad3. These data indicate that UCHL5 may contribute to the 
      pathogenesis of IPF and may be a potential therapeutic target.
FAU - Nan, Ling
AU  - Nan L
AD  - Department of Anesthesia, First Hospital of Jilin University, Changchun, China.
FAU - Jacko, Anastasia M
AU  - Jacko AM
AD  - Department of Medicine, Acute Lung Injury Center of Excellence, Department of 
      Cell Biology, University of Pittsburgh, Pittsburgh, PA, United States.
FAU - Tan, Jiangning
AU  - Tan J
AD  - Department of Medicine, Acute Lung Injury Center of Excellence, Department of 
      Cell Biology, University of Pittsburgh, Pittsburgh, PA, United States.
FAU - Wang, Dan
AU  - Wang D
AD  - Department of Anesthesia, First Hospital of Jilin University, Changchun, China.
FAU - Zhao, Jing
AU  - Zhao J
AD  - Department of Medicine, Acute Lung Injury Center of Excellence, Department of 
      Cell Biology, University of Pittsburgh, Pittsburgh, PA, United States.
FAU - Kass, Daniel J
AU  - Kass DJ
AD  - Department of Medicine, Acute Lung Injury Center of Excellence, Department of 
      Cell Biology, University of Pittsburgh, Pittsburgh, PA, United States.
FAU - Ma, Haichun
AU  - Ma H
AD  - Department of Anesthesia, First Hospital of Jilin University, Changchun, China.
FAU - Zhao, Yutong
AU  - Zhao Y
AD  - Department of Medicine, Acute Lung Injury Center of Excellence, Department of 
      Cell Biology, University of Pittsburgh, Pittsburgh, PA, United States.
LA  - eng
GR  - R01 HL112791/HL/NHLBI NIH HHS/United States
GR  - R01 HL091916/HL/NHLBI NIH HHS/United States
GR  - R01 GM115389/GM/NIGMS NIH HHS/United States
GR  - P01 HL114453/HL/NHLBI NIH HHS/United States
GR  - R01 HL126990/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20160908
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (3,5-bis((4-nitrophenyl)methylidene)-1-prop-2-enoylpiperidin-4-one)
RN  - 0 (Piperidones)
RN  - 0 (SMAD2 protein, human)
RN  - 0 (SMAD3 protein, human)
RN  - 0 (Smad2 Protein)
RN  - 0 (Smad2 protein, mouse)
RN  - 0 (Smad3 Protein)
RN  - 0 (Smad3 protein, mouse)
RN  - 0 (Transforming Growth Factor beta1)
RN  - 11056-06-7 (Bleomycin)
RN  - EC 3.4.19.12 (UCHL5 protein, human)
RN  - EC 3.4.19.12 (Ubiquitin Thiolesterase)
RN  - EC 3.4.19.12 (Uchl5 protein, mouse)
SB  - IM
MH  - Animals
MH  - Bleomycin/toxicity
MH  - Cell Line
MH  - Cells, Cultured
MH  - Disease Models, Animal
MH  - Humans
MH  - Idiopathic Pulmonary Fibrosis/etiology/*metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Piperidones/pharmacology
MH  - Protein Stability/drug effects
MH  - Proteolysis/drug effects
MH  - Signal Transduction/drug effects
MH  - Smad2 Protein/chemistry/*metabolism
MH  - Smad3 Protein/chemistry/*metabolism
MH  - Transforming Growth Factor beta1/*metabolism
MH  - Ubiquitin Thiolesterase/antagonists & inhibitors/*metabolism
MH  - Ubiquitination/drug effects
PMC - PMC5015047
EDAT- 2016/09/09 06:00
MHDA- 2018/06/05 06:00
PMCR- 2016/09/08
CRDT- 2016/09/09 06:00
PHST- 2016/05/03 00:00 [received]
PHST- 2016/08/22 00:00 [accepted]
PHST- 2016/09/09 06:00 [entrez]
PHST- 2016/09/09 06:00 [pubmed]
PHST- 2018/06/05 06:00 [medline]
PHST- 2016/09/08 00:00 [pmc-release]
AID - srep33116 [pii]
AID - 10.1038/srep33116 [doi]
PST - epublish
SO  - Sci Rep. 2016 Sep 8;6:33116. doi: 10.1038/srep33116.