{"doi":"10.1101/gad.352010.124","title":"E3 ligase substrate adaptor SPOP fine-tunes the UPR of pancreatic β cells","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.","journal":"Genes & Development","year":2024,"id":508131,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9458,"is_data_producer":true,"deposit_databanks":{"GEO":["GSE282084"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":306347,"name":"Matthew W. Haemmerle","orcid":null,"position":1,"is_corresponding":false},{"id":1236885,"name":"Sabyasachi Sen","orcid":"0000-0002-1685-4233","position":2,"is_corresponding":false},{"id":858386,"name":"Andrea V. Rozo","orcid":null,"position":3,"is_corresponding":false},{"id":1359795,"name":"Shristi Shrestha","orcid":"0000-0002-3395-7824","position":4,"is_corresponding":false},{"id":250517,"name":"Jeeyeon Cha","orcid":"0000-0002-0312-2391","position":5,"is_corresponding":false},{"id":229060,"name":"Hossein Fazelinia","orcid":"0000-0003-3074-5698","position":6,"is_corresponding":false},{"id":688393,"name":"Hua Ding","orcid":"0000-0001-5897-0534","position":7,"is_corresponding":false},{"id":1359796,"name":"Sam Preza","orcid":"0000-0003-3612-3662","position":8,"is_corresponding":false},{"id":705535,"name":"Juxiang Yang","orcid":null,"position":9,"is_corresponding":false},{"id":502799,"name":"Xiaodun Yang","orcid":"0000-0001-9253-9449","position":10,"is_corresponding":false},{"id":449848,"name":"Lori Sussel","orcid":"0000-0003-4672-7304","position":11,"is_corresponding":false},{"id":1196471,"name":"Juan R. Alvarez-Dominguez","orcid":null,"position":12,"is_corresponding":false},{"id":415494,"name":"Nicolai M. Doliba","orcid":"0000-0003-4598-9222","position":13,"is_corresponding":false},{"id":373726,"name":"Lynn A. Spruce","orcid":"0000-0001-9640-9158","position":14,"is_corresponding":false},{"id":361506,"name":"Rafael Arrojo e Drigo","orcid":"0000-0001-7712-013X","position":15,"is_corresponding":false},{"id":304326,"name":"Doris A. Stoffers","orcid":"0000-0003-2626-2124","position":16,"is_corresponding":false},{"id":723844,"name":"Alexis Oguh","orcid":null,"position":0,"is_corresponding":true}],"reference_count":109,"raw_metadata":null,"created_at":"2026-07-19T02:11:06.395600Z","pmid":"39797759","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}