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Both conditional ablation and overexpression of E2 SUMO-conjugating enzyme (UBC9) in mouse pancreatic beta cells result in impaired beta cell function

  • Xiaoyu He
  • Qiaohong Lai
  • Cai Chen
  • Na Li
  • Fei Sun
  • Wenting Huang
  • Shu Zhang
  • Qilin Yu
  • Ping Yang
  • Fei Xiong
  • Zhishui Chen
  • Quan Gong
  • Boxu Ren
  • Jianping Weng
  • Décio L. Eizirik
  • Zhiguang Zhou
  • Cong-Yi Wang



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.


Inducible beta cell-specific Ubc9 (also known as Ube2i) knockout (KO; Ubc9Δbeta) and transgenic (Ubc9Tg) 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.


Upon induction of Ubc9 deficiency, Ubc9Δbeta islets exhibited a 3.5-fold higher accumulation of reactive oxygen species (ROS) than Ubc9f/f control islets. Islets from Ubc9Δbeta 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 Ubc9Δbeta mice, while 90% of beta cell mass was lost by day 75. Diabetes onset was noted in some Ubc9Δbeta mice 8 weeks after induction of Ubc9 deficiency and all mice developed diabetes by 10 weeks following tamoxifen treatment. In contrast, Ubc9Tg beta cells displayed an increased antioxidant ability but impaired insulin secretion. Unlike Ubc9Δbeta mice, which spontaneously developed diabetes, Ubc9Tg 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.


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.


Diabetes Insulin content Insulin secretion NRF2 Oxidative stress Pancreatic beta cell SUMOylation UBC9 



Antioxidant response element


Chromatin immunoprecipitation




2′,7′-Dichlorodihydrofluorescein diacetate


Electrophoretic mobility shift assay










Nuclear factor erythroid 2-related factor 2


Tamoxifen-induced Ubc9 transgenic mouse model (controls)


Reactive oxygen species


Sentrin-specific protease 1




Small ubiquitin-like modifier


E2 SUMO-conjugating enzyme


Beta cell-specific Ubc9 knockout mouse model


Inducible Ubc9 transgenic mouse model


Ubc9flox mice


Beta cell-specific Ubc9 transgenic mouse model





We are grateful to D. Melton (Harvard University, Cambridge, MA, USA) for providing the Rip-CreER mice, and Q. Yang (University of Alabama, Birmingham, AL, USA) for providing the pCAG-CAT-X vector.

Data availability

All data generated or analysed during this study are included in this published article (and its ESM files).

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

CYW conceived the project. XH, QL, CC, NL, FS, WH, SZ and PY contributed to the acquisition of data, analysis and interpretation. XH wrote the manuscript. CYW, SZ, QY and FX were involved in designing the strategy to generate and genotype the Ubc9Δbeta and Ubc9Tg mouse lines. SZ, ZC, QG, BR, JW, DLE and ZZ contributed to analysis and interpretation of the data. CYW, DLE and ZZ contributed to the study design and manuscript preparation. All authors were involved in drafting the article or revising it critically, and all authors gave their approval for the final manuscript to be published. CYW is the guarantor of this work and takes full responsibility for the content of the manuscript.

Supplementary material

125_2017_4523_MOESM1_ESM.pdf (553 kb)
ESM (PDF 552 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Xiaoyu He
    • 1
  • Qiaohong Lai
    • 1
  • Cai Chen
    • 1
  • Na Li
    • 1
  • Fei Sun
    • 1
  • Wenting Huang
    • 1
  • Shu Zhang
    • 1
  • Qilin Yu
    • 1
  • Ping Yang
    • 1
  • Fei Xiong
    • 1
  • Zhishui Chen
    • 1
  • Quan Gong
    • 2
  • Boxu Ren
    • 2
  • Jianping Weng
    • 3
  • Décio L. Eizirik
    • 4
  • Zhiguang Zhou
    • 5
  • Cong-Yi Wang
    • 1
  1. 1.The Center for Biomedical Research, Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Health, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanPeople’s Republic of China
  2. 2.Medical College of Yangtze UniversityJingzhouPeople’s Republic of China
  3. 3.Department of Endocrinology and Metabolism, The Third Affiliated HospitalSun Yat-Sen UniversityGuangzhouPeople’s Republic of China
  4. 4.ULB Center for Diabetes Research, Université Libre de BruxellesBrusselsBelgium
  5. 5.Diabetes Center, The Second Xiangya Hospital, Institute of Metabolism and EndocrinologyCentral South UniversityChangshaPeople’s Republic of China

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