Inhibition of glycogen synthase kinase-3 enhances NRF2 protein stability, nuclear localisation and target gene transcription in pancreatic beta cells

• DOI: 10.1016/j.redox.2024.103117
• Publication Date: 2024-03-07T18:09:49Z
• Authors: Chinmai Patibandla; Lidy van Aalten; Albena T. Dinkova...; Tadashi Honda; Antonio Cuadrado; Raquel Fernández-...; Alison D. McNeilly; John D. Hayes; James Cantley; Calum Sutherland
• Keywords: Cullin; KEAP1; GSK3B

Accumulation of reactive oxygen species (i.e., oxidative stress) is a leading cause beta cell dysfunction and apoptosis in diabetes. NRF2 (NF-E2 p45-related factor-2) regulates the adaptation to stress, its activity negatively regulated by redox-sensitive CUL3 (cullin-3) ubiquitin ligase substrate adaptor KEAP1 (Kelch-like ECH-associated protein-1). Additionally, repressed insulin-regulated Glycogen Synthase Kinase-3 (GSK3). We have demonstrated that phosphorylation GSK3 enhances β-TrCP (beta-transducin repeat-containing protein) binding ubiquitylation CUL1 (cullin-1), resulting increased proteasomal degradation NRF2. Thus, we hypothesise inhibition or upregulates so protects cells against stress. found treating pancreatic line INS-1832/13 with inhibitor TBE31 significantly enhanced protein levels. The presence CT99021 β-TrCP-NRF2 protein-protein interaction PHAR, along TBE31, resulted prolonged stability nuclear localisation (p < 0.05). TBE31-mediated induction NRF2-target genes encoding NAD(P)H quinone oxidoreductase 1 (Nqo1), glutamate-cysteine modifier (Gclm) subunit heme oxygenase (Hmox1) was PHAR (P 0.05) both isolated mouse islets. Identical results were obtained using structurally distinct inhibitors sulforaphane. In summary, demonstrate β-TrCP/CUL1 regulate NRF2, enhancing impact regulation, contributes redox status cells. Inhibition GSK3, may represent strategy protect from