Both conditional ablation and overexpression of E2 SUMO-conjugating enzyme (UBC9) in mouse pancreatic beta cells result in impaired beta cell function
- PMID: 29299635
- DOI: 10.1007/s00125-017-4523-9
Both conditional ablation and overexpression of E2 SUMO-conjugating enzyme (UBC9) in mouse pancreatic beta cells result in impaired beta cell function
Abstract
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; 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.
Results: 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.
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.
Keywords: Diabetes; Insulin content; Insulin secretion; NRF2; Oxidative stress; Pancreatic beta cell; SUMOylation; UBC9.
Comment in
-
A post-translational balancing act: the good and the bad of SUMOylation in pancreatic islets.Diabetologia. 2018 Apr;61(4):775-779. doi: 10.1007/s00125-017-4543-5. Epub 2018 Jan 12. Diabetologia. 2018. PMID: 29330559
Similar articles
-
A post-translational balancing act: the good and the bad of SUMOylation in pancreatic islets.Diabetologia. 2018 Apr;61(4):775-779. doi: 10.1007/s00125-017-4543-5. Epub 2018 Jan 12. Diabetologia. 2018. PMID: 29330559
-
NRF2 is required for neonatal mouse beta cell growth by maintaining redox balance and promoting mitochondrial biogenesis and function.Diabetologia. 2024 Mar;67(3):547-560. doi: 10.1007/s00125-023-06071-7. Epub 2024 Jan 11. Diabetologia. 2024. PMID: 38206362
-
Loss of ubiquitin-conjugating enzyme E2 (Ubc9) in macrophages exacerbates multiple low-dose streptozotocin-induced diabetes by attenuating M2 macrophage polarization.Cell Death Dis. 2019 Nov 26;10(12):892. doi: 10.1038/s41419-019-2130-z. Cell Death Dis. 2019. PMID: 31767832 Free PMC article.
-
Mechanisms and functions of SUMOylation in health and disease: a review focusing on immune cells.J Biomed Sci. 2024 Jan 27;31(1):16. doi: 10.1186/s12929-024-01003-y. J Biomed Sci. 2024. PMID: 38280996 Free PMC article. Review.
-
Targeting Ubc9 for cancer therapy.Expert Opin Ther Targets. 2005 Dec;9(6):1203-16. doi: 10.1517/14728222.9.6.1203. Expert Opin Ther Targets. 2005. PMID: 16300471 Review.
Cited by
-
Fluvoxamine inhibits Th1 and Th17 polarization and function by repressing glycolysis to attenuate autoimmune progression in type 1 diabetes.Mol Med. 2024 Feb 5;30(1):23. doi: 10.1186/s10020-024-00791-1. Mol Med. 2024. PMID: 38317106 Free PMC article.
-
Ubc9 regulates the expression of MHC II in dendritic cells to enhance DSS-induced colitis by mediating RBPJ SUMOylation.Cell Death Dis. 2023 Nov 13;14(11):737. doi: 10.1038/s41419-023-06266-1. Cell Death Dis. 2023. PMID: 37957143 Free PMC article.
-
Regulation of insulin secretion by the post-translational modifications.Front Cell Dev Biol. 2023 Aug 4;11:1217189. doi: 10.3389/fcell.2023.1217189. eCollection 2023. Front Cell Dev Biol. 2023. PMID: 37601108 Free PMC article. Review.
-
An ERK5-NRF2 Axis Mediates Senescence-Associated Stemness and Atherosclerosis.Circ Res. 2023 Jun 23;133(1):25-44. doi: 10.1161/CIRCRESAHA.122.322017. Epub 2023 Jun 2. Circ Res. 2023. PMID: 37264926 Free PMC article.
-
Targeting protein modifications in metabolic diseases: molecular mechanisms and targeted therapies.Signal Transduct Target Ther. 2023 May 27;8(1):220. doi: 10.1038/s41392-023-01439-y. Signal Transduct Target Ther. 2023. PMID: 37244925 Free PMC article. Review.
References
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
Research Materials
Miscellaneous