PMID- 32060407
OWN - NLM
STAT- MEDLINE
DCOM- 20201019
LR  - 20230216
IS  - 1530-0307 (Electronic)
IS  - 0023-6837 (Print)
IS  - 0023-6837 (Linking)
VI  - 100
IP  - 6
DP  - 2020 Jun
TI  - Wolfram syndrome 1 gene regulates pathways maintaining beta-cell health and 
      survival.
PG  - 849-862
LID - 10.1038/s41374-020-0408-5 [doi]
AB  - Wolfram Syndrome 1 (WFS1) protein is an endoplasmic reticulum (ER) factor whose 
      deficiency results in juvenile-onset diabetes secondary to cellular dysfunction 
      and apoptosis. The mechanisms guiding beta-cell outcomes secondary to WFS1 function, 
      however, remain unclear. Here, we show that WFS1 preserves normal beta-cell 
      physiology by promoting insulin biosynthesis and negatively regulating ER stress. 
      Depletion of Wfs1 in vivo and in vitro causes functional defects in 
      glucose-stimulated insulin secretion and insulin content, triggering 
      Chop-mediated apoptotic pathways. Genetic proof of concept studies coupled with 
      RNA-seq reveal that increasing WFS1 confers a functional and a survival advantage 
      to beta-cells under ER stress by increasing insulin gene expression and 
      downregulating the Chop-Trib3 axis, thereby activating Akt pathways. Remarkably, 
      WFS1 and INS levels are reduced in type-2 diabetic (T2DM) islets, suggesting that 
      WFS1 may contribute to T2DM beta-cell pathology. Taken together, this work reveals 
      essential pathways regulated by WFS1 to control beta-cell survival and function 
      primarily through preservation of ER homeostasis.
FAU - Abreu, Damien
AU  - Abreu D
AD  - Department of Medicine, Division of Endocrinology, Metabolism, and Lipid 
      Research, Washington University School of Medicine, St. Louis, MO, 63110, USA.
AD  - Medical Scientist Training Program, Washington University School of Medicine, St. 
      Louis, MO, 63110, USA.
FAU - Asada, Rie
AU  - Asada R
AD  - Department of Medicine, Division of Endocrinology, Metabolism, and Lipid 
      Research, Washington University School of Medicine, St. Louis, MO, 63110, USA.
AD  - Department of Biochemistry, Institute of Biomedical & Health Science, Hiroshima 
      University, Hiroshima, 734-8553, Japan.
FAU - Revilla, John M P
AU  - Revilla JMP
AD  - Department of Medicine, Division of Endocrinology, Metabolism, and Lipid 
      Research, Washington University School of Medicine, St. Louis, MO, 63110, USA.
FAU - Lavagnino, Zeno
AU  - Lavagnino Z
AD  - Department of Cell Biology and Physiology, Washington University School of 
      Medicine, St. Louis, MO, 63110, USA.
AD  - Experimental Imaging Center DIBIT, IRCCS Ospedale San Raffaele, 20132, Milan, 
      Italy.
FAU - Kries, Kelly
AU  - Kries K
AD  - Department of Medicine, Division of Endocrinology, Metabolism, and Lipid 
      Research, Washington University School of Medicine, St. Louis, MO, 63110, USA.
FAU - Piston, David W
AU  - Piston DW
AD  - Department of Cell Biology and Physiology, Washington University School of 
      Medicine, St. Louis, MO, 63110, USA.
FAU - Urano, Fumihiko
AU  - Urano F
AUID- ORCID: 0000-0002-9944-6293
AD  - Department of Medicine, Division of Endocrinology, Metabolism, and Lipid 
      Research, Washington University School of Medicine, St. Louis, MO, 63110, USA. 
      urano@wustl.edu.
AD  - Department of Pathology and Immunology, Washington University School of Medicine, 
      St. Louis, MO, 63110, USA. urano@wustl.edu.
LA  - eng
GR  - UH3 TR002065/TR/NCATS NIH HHS/United States
GR  - F30 DK111070/DK/NIDDK NIH HHS/United States
GR  - P30 CA091842/CA/NCI NIH HHS/United States
GR  - UL1 TR000448/TR/NCATS NIH HHS/United States
GR  - P60 DK020579/DK/NIDDK NIH HHS/United States
GR  - R01 DK112921/DK/NIDDK NIH HHS/United States
GR  - P30 DK020579/DK/NIDDK NIH HHS/United States
GR  - UL1 TR002345/TR/NCATS NIH HHS/United States
GR  - UH2 TR002065/TR/NCATS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200214
PL  - United States
TA  - Lab Invest
JT  - Laboratory investigation; a journal of technical methods and pathology
JID - 0376617
RN  - 0 (Blood Glucose)
RN  - 0 (Insulin)
RN  - 0 (Membrane Proteins)
RN  - 0 (wolframin protein)
SB  - IM
MH  - Animals
MH  - Blood Glucose/analysis/metabolism
MH  - Cell Line
MH  - Cells, Cultured
MH  - Endoplasmic Reticulum Stress/physiology
MH  - Humans
MH  - Insulin/analysis/metabolism
MH  - *Insulin-Secreting Cells/cytology/metabolism
MH  - *Membrane Proteins/genetics/metabolism/physiology
MH  - Mice, Knockout
MH  - Signal Transduction/physiology
MH  - Wolfram Syndrome
PMC - PMC7286786
MID - NIHMS1556896
COIS- Disclosure/Conflict of Interest The authors declare no competing interests 
      relevant to this article.
EDAT- 2020/02/16 06:00
MHDA- 2020/10/21 06:00
PMCR- 2020/08/14
CRDT- 2020/02/16 06:00
PHST- 2019/07/14 00:00 [received]
PHST- 2020/02/04 00:00 [accepted]
PHST- 2020/02/03 00:00 [revised]
PHST- 2020/02/16 06:00 [pubmed]
PHST- 2020/10/21 06:00 [medline]
PHST- 2020/02/16 06:00 [entrez]
PHST- 2020/08/14 00:00 [pmc-release]
AID - S0023-6837(22)00461-5 [pii]
AID - 10.1038/s41374-020-0408-5 [doi]
PST - ppublish
SO  - Lab Invest. 2020 Jun;100(6):849-862. doi: 10.1038/s41374-020-0408-5. Epub 2020 
      Feb 14.