1. E3 ligase substrate adaptor SPOP fine-tunes the UPR of pancreatic β cells.
- Author
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Oguh AU, Haemmerle MW, Sen S, Rozo AV, Shrestha S, Cartailler JP, Fazelinia H, Ding H, Preza S, Yang J, Yang X, Sussel L, Alvarez-Dominguez JR, Doliba N, Spruce LA, Arrojo E Drigo R, and Stoffers DA
- Subjects
- Animals, Mice, Ubiquitin-Protein Ligases metabolism, Ubiquitin-Protein Ligases genetics, Mice, Knockout, Insulin metabolism, Glucose metabolism, Insulin Secretion genetics, Humans, Protein Serine-Threonine Kinases metabolism, Protein Serine-Threonine Kinases genetics, Endoribonucleases metabolism, Endoribonucleases genetics, Signal Transduction, Transcription Factors metabolism, Transcription Factors genetics, Endoplasmic Reticulum Stress, Proteolysis, Ubiquitin-Protein Ligase Complexes, Insulin-Secreting Cells metabolism, Unfolded Protein Response physiology, Repressor Proteins metabolism, Repressor Proteins genetics, X-Box Binding Protein 1 metabolism, X-Box Binding Protein 1 genetics, Nuclear Proteins metabolism, Nuclear Proteins genetics
- Abstract
The Cullin-3 E3 ligase adaptor protein SPOP targets proteins for ubiquitination and proteasomal degradation. We previously established the β-cell transcription factor (TF) and human diabetes gene PDX1 as an SPOP substrate, suggesting a functional role for SPOP in the β cell. Here, we generated a β-cell-specific Spop deletion mouse strain ( Spop
βKO ) and found that Spop is necessary to prevent aberrant basal insulin secretion and for maintaining glucose-stimulated insulin secretion through impacts on glycolysis and glucose-stimulated calcium flux. Integration of proteomic, TF-regulatory gene network, and biochemical analyses identified XBP1 as a functionally important SPOP substrate in pancreatic β cells. Furthermore, loss of SPOP strengthened the IRE1α-XBP1 axis of unfolded protein response (UPR) signaling. ER stress promoted proteasomal degradation of SPOP, supporting a model whereby SPOP fine-tunes XBP1 activation during the UPR. These results position SPOP as a regulator of β-cell function and proper UPR activation., (© 2025 Oguh et al.; Published by Cold Spring Harbor Laboratory Press.)- Published
- 2025
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