PMID- 24879150
OWN - NLM
STAT- MEDLINE
DCOM- 20150511
LR  - 20211021
IS  - 1554-8635 (Electronic)
IS  - 1554-8627 (Print)
IS  - 1554-8627 (Linking)
VI  - 10
IP  - 6
DP  - 2014 Jun
TI  - UCHL1 deficiency exacerbates human islet amyloid polypeptide toxicity in beta-cells: 
      evidence of interplay between the ubiquitin/proteasome system and autophagy.
PG  - 1004-14
LID - 10.4161/auto.28478 [doi]
AB  - The islet in type 2 diabetes mellitus (T2DM) is characterized by a deficit in 
      beta-cells and increased beta-cell apoptosis attributable at least in part to 
      intracellular toxic oligomers of IAPP (islet amyloid polypeptide). beta-cells of 
      individuals with T2DM are also characterized by accumulation of polyubiquitinated 
      proteins and deficiency in the deubiquitinating enzyme UCHL1 (ubiquitin 
      carboxyl-terminal esterase L1 [ubiquitin thiolesterase]), accounting for a 
      dysfunctional ubiquitin/proteasome system. In the present study, we used mouse 
      genetics to elucidate in vivo whether a partial deficit in UCHL1 enhances the 
      vulnerability of beta-cells to human-IAPP (hIAPP) toxicity, and thus accelerates 
      diabetes onset. We further investigated whether a genetically induced deficit in 
      UCHL1 function in beta-cells exacerbates hIAPP-induced alteration of the autophagy 
      pathway in vivo. We report that a deficit in UCHL1 accelerated the onset of 
      diabetes in hIAPP transgenic mice, due to a decrease in beta-cell mass caused by 
      increased beta-cell apoptosis. We report that UCHL1 dysfunction aggravated the 
      hIAPP-induced defect in the autophagy/lysosomal pathway, illustrated by the 
      marked accumulation of autophagosomes and cytoplasmic inclusions positive for 
      SQSTM1/p62 and polyubiquitinated proteins with lysine 63-specific ubiquitin 
      chains. Collectively, this study shows that defective UCHL1 function may be an 
      early contributor to vulnerability of pancreatic beta-cells for protein misfolding 
      and proteotoxicity, hallmark defects in islets of T2DM. Also, given that 
      deficiency in UCHL1 exacerbated the defective autophagy/lysosomal degradation 
      characteristic of hIAPP proteotoxicity, we demonstrate a previously unrecognized 
      role of UCHL1 in the function of the autophagy/lysosomal pathway in beta-cells.
FAU - Costes, Safia
AU  - Costes S
AD  - Larry L. Hillblom Islet Research Center; David Geffen School of Medicine; 
      University of California, Los Angeles; Los Angeles, CA USA.
FAU - Gurlo, Tatyana
AU  - Gurlo T
AD  - Larry L. Hillblom Islet Research Center; David Geffen School of Medicine; 
      University of California, Los Angeles; Los Angeles, CA USA.
FAU - Rivera, Jacqueline F
AU  - Rivera JF
AD  - Larry L. Hillblom Islet Research Center; David Geffen School of Medicine; 
      University of California, Los Angeles; Los Angeles, CA USA.
FAU - Butler, Peter C
AU  - Butler PC
AD  - Larry L. Hillblom Islet Research Center; David Geffen School of Medicine; 
      University of California, Los Angeles; Los Angeles, CA USA.
LA  - eng
GR  - R01 DK059579/DK/NIDDK NIH HHS/United States
GR  - DK059579/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Autophagy
JT  - Autophagy
JID - 101265188
RN  - 0 (Islet Amyloid Polypeptide)
RN  - 0 (Mutant Proteins)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Ubiquitin)
RN  - 0 (Ubiquitin carboxyl-Terminal Hydrolase L-1, mouse)
RN  - EC 3.4.19.12 (Ubiquitin Thiolesterase)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
SB  - IM
MH  - Animals
MH  - Apoptosis
MH  - Autophagy/genetics/*physiology
MH  - Diabetes Mellitus, Type 2/genetics/metabolism/pathology
MH  - Humans
MH  - Insulin Resistance
MH  - Insulin-Secreting Cells/*metabolism/*pathology
MH  - Islet Amyloid Polypeptide/genetics/*metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Mutant Strains
MH  - Mice, Transgenic
MH  - Mutant Proteins/genetics/metabolism
MH  - Proteasome Endopeptidase Complex/metabolism
MH  - Recombinant Proteins/genetics/metabolism
MH  - Ubiquitin/metabolism
MH  - Ubiquitin Thiolesterase/*deficiency/genetics/metabolism
PMC - PMC4091165
OTO - NOTNLM
OT  - SQSTM1/p62
OT  - apoptosis
OT  - autophagy
OT  - diabetes
OT  - islet amyloid polypeptide
OT  - ubiquitin carboxyl-terminal esterase L1
OT  - beta-cell
EDAT- 2014/06/01 06:00
MHDA- 2015/05/12 06:00
PMCR- 2015/06/01
CRDT- 2014/06/01 06:00
PHST- 2014/06/01 06:00 [entrez]
PHST- 2014/06/01 06:00 [pubmed]
PHST- 2015/05/12 06:00 [medline]
PHST- 2015/06/01 00:00 [pmc-release]
AID - 28478 [pii]
AID - 2013AUTO0123R2 [pii]
AID - 10.4161/auto.28478 [doi]
PST - ppublish
SO  - Autophagy. 2014 Jun;10(6):1004-14. doi: 10.4161/auto.28478.