PMID- 29299635
OWN - NLM
STAT- MEDLINE
DCOM- 20190103
LR  - 20200225
IS  - 1432-0428 (Electronic)
IS  - 0012-186X (Linking)
VI  - 61
IP  - 4
DP  - 2018 Apr
TI  - Both conditional ablation and overexpression of E2 SUMO-conjugating enzyme (UBC9) 
      in mouse pancreatic beta cells result in impaired beta cell function.
PG  - 881-895
LID - 10.1007/s00125-017-4523-9 [doi]
AB  - AIMS/HYPOTHESIS: Post-translational attachment of a small ubiquitin-like modifier 
      (SUMO) to the lysine (K) residue(s) of target proteins (SUMOylation) is an 
      evolutionary conserved regulatory mechanism. This modification has previously 
      been demonstrated to be implicated in the control of a remarkably versatile 
      regulatory mechanism of cellular processes. However, the exact regulatory role 
      and biological actions of the E2 SUMO-conjugating enzyme (UBC9)-mediated 
      SUMOylation function in pancreatic beta cells has remained elusive. METHODS: 
      Inducible beta cell-specific Ubc9 (also known as Ube2i) knockout (KO; 
      Ubc9(Deltabeta)) and transgenic (Ubc9(Tg)) mice were employed to address the impact 
      of SUMOylation on beta cell viability and functionality. Ubc9 deficiency or 
      overexpression was induced at 8 weeks of age using tamoxifen. To study the 
      mechanism involved, we closely examined the regulation of the transcription 
      factor nuclear factor erythroid 2-related factor 2 (NRF2) through SUMOylation in 
      beta cells. RESULTS: Upon induction of Ubc9 deficiency, Ubc9(Deltabeta) islets 
      exhibited a 3.5-fold higher accumulation of reactive oxygen species (ROS) than 
      Ubc9(f/f) control islets. Islets from Ubc9(Deltabeta) mice also had decreased insulin 
      content and loss of beta cell mass after tamoxifen treatment. Specifically, at 
      day 45 after Ubc9 deletion only 40% of beta cell mass remained in Ubc9(Deltabeta) 
      mice, while 90% of beta cell mass was lost by day 75. Diabetes onset was noted in 
      some Ubc9(Deltabeta) mice 8 weeks after induction of Ubc9 deficiency and all mice 
      developed diabetes by 10 weeks following tamoxifen treatment. In contrast, 
      Ubc9(Tg) beta cells displayed an increased antioxidant ability but impaired 
      insulin secretion. Unlike Ubc9(Deltabeta) mice, which spontaneously developed 
      diabetes, Ubc9(Tg) mice preserved normal non-fasting blood glucose levels without 
      developing diabetes. It was noted that SUMOylation of NRF2 promoted its nuclear 
      expression along with enhanced transcriptional activity, thereby preventing ROS 
      accumulation in beta cells. CONCLUSIONS/INTERPRETATION: SUMOylation function is 
      required to protect against oxidative stress in beta cells; this mechanism is, at 
      least in part, carried out by the regulation of NRF2 activity to enhance ROS 
      detoxification. Homeostatic SUMOylation is also likely to be essential for 
      maintaining beta cell functionality.
FAU - He, Xiaoyu
AU  - He X
AD  - The Center for Biomedical Research, Key Laboratory of Organ Transplantation, 
      Ministry of Education and Ministry of Health, Tongji Hospital, Tongji Medical 
      College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 
      Wuhan, 430030, People's Republic of China.
FAU - Lai, Qiaohong
AU  - Lai Q
AD  - The Center for Biomedical Research, Key Laboratory of Organ Transplantation, 
      Ministry of Education and Ministry of Health, Tongji Hospital, Tongji Medical 
      College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 
      Wuhan, 430030, People's Republic of China.
FAU - Chen, Cai
AU  - Chen C
AD  - The Center for Biomedical Research, Key Laboratory of Organ Transplantation, 
      Ministry of Education and Ministry of Health, Tongji Hospital, Tongji Medical 
      College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 
      Wuhan, 430030, People's Republic of China.
FAU - Li, Na
AU  - Li N
AD  - The Center for Biomedical Research, Key Laboratory of Organ Transplantation, 
      Ministry of Education and Ministry of Health, Tongji Hospital, Tongji Medical 
      College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 
      Wuhan, 430030, People's Republic of China.
FAU - Sun, Fei
AU  - Sun F
AD  - The Center for Biomedical Research, Key Laboratory of Organ Transplantation, 
      Ministry of Education and Ministry of Health, Tongji Hospital, Tongji Medical 
      College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 
      Wuhan, 430030, People's Republic of China.
FAU - Huang, Wenting
AU  - Huang W
AD  - The Center for Biomedical Research, Key Laboratory of Organ Transplantation, 
      Ministry of Education and Ministry of Health, Tongji Hospital, Tongji Medical 
      College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 
      Wuhan, 430030, People's Republic of China.
FAU - Zhang, Shu
AU  - Zhang S
AD  - The Center for Biomedical Research, Key Laboratory of Organ Transplantation, 
      Ministry of Education and Ministry of Health, Tongji Hospital, Tongji Medical 
      College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 
      Wuhan, 430030, People's Republic of China.
FAU - Yu, Qilin
AU  - Yu Q
AD  - The Center for Biomedical Research, Key Laboratory of Organ Transplantation, 
      Ministry of Education and Ministry of Health, Tongji Hospital, Tongji Medical 
      College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 
      Wuhan, 430030, People's Republic of China.
FAU - Yang, Ping
AU  - Yang P
AD  - The Center for Biomedical Research, Key Laboratory of Organ Transplantation, 
      Ministry of Education and Ministry of Health, Tongji Hospital, Tongji Medical 
      College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 
      Wuhan, 430030, People's Republic of China.
FAU - Xiong, Fei
AU  - Xiong F
AD  - The Center for Biomedical Research, Key Laboratory of Organ Transplantation, 
      Ministry of Education and Ministry of Health, Tongji Hospital, Tongji Medical 
      College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 
      Wuhan, 430030, People's Republic of China.
FAU - Chen, Zhishui
AU  - Chen Z
AD  - The Center for Biomedical Research, Key Laboratory of Organ Transplantation, 
      Ministry of Education and Ministry of Health, Tongji Hospital, Tongji Medical 
      College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 
      Wuhan, 430030, People's Republic of China.
FAU - Gong, Quan
AU  - Gong Q
AD  - Medical College of Yangtze University, Jingzhou, Hubei, People's Republic of 
      China.
FAU - Ren, Boxu
AU  - Ren B
AD  - Medical College of Yangtze University, Jingzhou, Hubei, People's Republic of 
      China.
FAU - Weng, Jianping
AU  - Weng J
AD  - Department of Endocrinology and Metabolism, The Third Affiliated Hospital, Sun 
      Yat-Sen University, Guangzhou, People's Republic of China.
FAU - Eizirik, Decio L
AU  - Eizirik DL
AD  - ULB Center for Diabetes Research, Universite Libre de Bruxelles, Brussels, 
      Belgium.
FAU - Zhou, Zhiguang
AU  - Zhou Z
AD  - Diabetes Center, The Second Xiangya Hospital, Institute of Metabolism and 
      Endocrinology, Central South University, Changsha, 410011, People's Republic of 
      China. zhouzg@hotmail.com.
FAU - Wang, Cong-Yi
AU  - Wang CY
AD  - The Center for Biomedical Research, Key Laboratory of Organ Transplantation, 
      Ministry of Education and Ministry of Health, Tongji Hospital, Tongji Medical 
      College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 
      Wuhan, 430030, People's Republic of China. wangcy@tjh.tjmu.edu.cn.
LA  - eng
GR  - T2D systems (GA667191)/Horizon 2020 program/International
GR  - 81530024, 9174920038, 81471046, 81470988, and 8167/National Natural Science 
      Foundation of China/International
GR  - 2016YFC1305002 and 2017YFC1309603/Ministry of Science and Technology of the 
      People's Republic of China/International
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180103
PL  - Germany
TA  - Diabetologia
JT  - Diabetologia
JID - 0006777
RN  - 0 (Antioxidants)
RN  - 0 (Blood Glucose)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (Nfe2l2 protein, mouse)
RN  - 0 (Reactive Oxygen Species)
RN  - EC 2.3.2.23 (Ubiquitin-Conjugating Enzymes)
RN  - EC 6.3.2.- (ubiquitin-conjugating enzyme UBC9)
RN  - K3Z4F929H6 (Lysine)
SB  - IM
CIN - Diabetologia. 2018 Apr;61(4):775-779. PMID: 29330559
MH  - Animals
MH  - Antioxidants/metabolism
MH  - Apoptosis
MH  - Blood Glucose/analysis
MH  - Glucose Tolerance Test
MH  - HEK293 Cells
MH  - Humans
MH  - Insulin-Secreting Cells/cytology/*enzymology
MH  - Islets of Langerhans/cytology/physiopathology
MH  - Lysine/chemistry
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - NF-E2-Related Factor 2/genetics
MH  - Oxidative Stress
MH  - Reactive Oxygen Species/metabolism
MH  - Sumoylation
MH  - Time Factors
MH  - Ubiquitin-Conjugating Enzymes/genetics/*metabolism
OTO - NOTNLM
OT  - Diabetes
OT  - Insulin content
OT  - Insulin secretion
OT  - NRF2
OT  - Oxidative stress
OT  - Pancreatic beta cell
OT  - SUMOylation
OT  - UBC9
EDAT- 2018/01/05 06:00
MHDA- 2019/01/04 06:00
CRDT- 2018/01/05 06:00
PHST- 2017/08/01 00:00 [received]
PHST- 2017/11/16 00:00 [accepted]
PHST- 2018/01/05 06:00 [pubmed]
PHST- 2019/01/04 06:00 [medline]
PHST- 2018/01/05 06:00 [entrez]
AID - 10.1007/s00125-017-4523-9 [pii]
AID - 10.1007/s00125-017-4523-9 [doi]
PST - ppublish
SO  - Diabetologia. 2018 Apr;61(4):881-895. doi: 10.1007/s00125-017-4523-9. Epub 2018 
      Jan 3.