E3 ligase substrate adaptor SPOP fine-tunes the UPR of pancreatic β 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 <i>Spop</i> deletion mouse strain (<i>Spop</i> <sup>βKO</sup>) and found that <i>Spop</i> 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.

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Publication Details

Journal
Genes & Development
Published
2024-12-30
DOI
https://doi.org/10.1101/gad.352010.124
Primary Topic
Endoplasmic Reticulum Stress and Disease
Type
article

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article

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

Doris A. Stoffers, Andrea V. Rozo, Sam Preza, Jean‐Philippe Cartailler et al.
Genes & Development
Endoplasmic Reticulum Stress and Disease
article

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

Doris A. Stoffers, Andrea V. Rozo, Sam Preza, Jean‐Philippe Cartailler, Hossein Fazelinia, Nicolai M. Doliba, Alexis Oguh, Lynn A. Spruce, Rafael Arrojo e Drigo, Matthew W. Haemmerle, Shristi Shrestha, Xiaodun Yang, Lori Sussel, Juxiang Yang, Hua Ding, Sabyasachi Sen, Juan R. Alvarez-Dominguez
article en

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 <i>Spop</i> deletion mouse strain (<i>Spop</i> <sup>βKO</sup>) and found that <i>Spop</i> 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.

Genes & DevelopmentVol. 39(3-4)
Children's Hospital of Philadelphia (US), Vanderbilt University (US), University of Colorado Anschutz Medical Campus (US), University of Pennsylvania (US)
Children's Hospital of Philadelphia, Vanderbilt University, University of Pennsylvania, National Institutes of Health, Diabetes Research Center
Good health and well-being
Endoplasmic Reticulum Stress and Disease
DOIOpen Access PDFOpenAlex
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