E3 ligase substrate adaptor SPOP fine tunes the UPR of pancreatic beta cells

The Cullin-3 E3 ligase adaptor protein, SPOP, targets proteins for ubiquitination and proteasomal degradation. We previously established the ß cell transcription factor (TF) and human diabetes gene PDX1 as an SPOP substrate, suggesting a functional role for SPOP in the ß cell. Here, we generated a ß cell specific Spop deletion mouse strain (SpopßKO) and found that Spop is necessary to prevent aberrant basal insulin secretion and for maintaining glucose- stimulated insulin secretion (GSIS) 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 ß cells. Further, loss of SPOP strengthened the IRE1a-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 ß cell function and proper UPR activation. Overall design: Pancreatic islets were isolated from 12-week-old female control (Spopfl/fl) mice and mice with beta cell specific deletion of Spop (SpopßKO). Mice are on a C57BL/6 background.