A post-translational balancing act: the good and the bad of SUMOylation in pancreatic islets

Abstract

Post-translational modification of proteins contributes to the control of cell function and survival. The balance of these in insulin-producing pancreatic beta cells is important for the maintenance of glucose homeostasis. Protection from the damaging effects of reactive oxygen species is required for beta cell survival, but if this happens at the expense of insulin secretory function then the ability of islets to respond to changing metabolic conditions may be compromised. In this issue of Diabetologia, He et al (https://doi.org/10.1007/s00125-017-4523-9) show that post-translational attachment of small ubiquitin-like modifier (SUMO) to target lysine residues (SUMOylation) strikes an important balance between the protection of beta cells from oxidative stress and the maintenance of insulin secretory function. They show that SUMOylation is required to stabilise nuclear factor erythroid 2-related factor 2 (NRF2) and increase antioxidant gene expression. Decreasing SUMOylation in beta cells impairs their antioxidant capacity, causes cell death, hyperglycaemia, and increased sensitivity to streptozotocin-induced diabetes, while increasing SUMOylation is protective. However, this protection from overt diabetes occurs in concert with glucose intolerance due to impaired beta cell function. A possible role for SUMOylation as a key factor balancing beta cell protection vs beta cell responsiveness to metabolic cues is discussed in this Commentary.

β-Cell Knockout of SENP1 Reduces Responses to Incretins and Worsens Oral Glucose Tolerance in High-Fat Diet–Fed Mice

“…Somewhat contradicting this, overexpression of SENP1 induces apoptosis in β-cells ( 12 ), and mice lacking the SUMO-conjugating enzyme Ubc9 develop diabetes as a result of β-cell death ( 13 ). Effectively, SUMOylation appears required for β-cell viability at the cost of β-cell function ( 14 ). It remains unknown whether the deSUMOylating enzyme SENP1 is required for the facilitation of insulin secretory responses and glucose tolerance under metabolic stress, such as high-fat diet (HFD), or conversely, whether loss of SENP1 would protect against glucose intolerance by preserving β-cell mass and insulin secretion.…”

Pathways linked to unresolved inflammation and airway remodelling characterize the transcriptome in two independent severe asthma cohorts

“…Resulting from cytokine stimulation, the p65 subunit of NF‐κB translocates to the nucleus, binds to PIAS1 and inhibits cytokine‐induced NF‐κB‐dependent gene activation, 23 promoting transforming growth factor‐β1 (TGF‐β1)‐induced activation of smooth muscle α‐actin 26 . The NRF2 anti‐oxidant stress pathway is also a target for SUMOylation, 27 and this interaction has been shown to affect the oxidative stress response to respiratory syncytial virus 28 . In the mouse, the NRF2 oxidative stress signalling pathway has been shown to contribute to airway inflammation and remodelling, by promoting goblet cell hyperplasia, and hyperresponsiveness in allergen‐mediated asthma 29 .…”

The Role of Lysine 63-Linked Ubiquitylation in Health and Disease

“…Among these, also post-translational modification has been recognized to play a role. SUMOylation, a post-translational modification consisting in covalent attachment to target proteins of the small ubiquitin-like modifier (SUMO) peptides, has been recently described as a key event regulating β-cell survival and function [57]. Different cytokines can induce autoimmune destruction of pancreatic β-cell through the modulation of several intracellular signaling pathways characterized by the activation of phosphorylation and ubiquitylation events, including K63 ubiquitylation, in the cells.…”