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 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 (SpopβKO) 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 β cells. Further, 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. Pancreatic islets were isolated from 12-week-old female control (Spopfl/fl) mice and mice with beta cell specific deletion of Spop (SpopβKO). Mice are on a C57BL/6 background.