{"database":"MassIVE","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://massive-ftp.ucsd.edu/v07/MSV000094310/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"submitter":["Michael Kalwat","Amber L. Mosley"],"full_dataset_link":["https://massive.ucsd.edu/ProteoSAFe/dataset.jsp?task=0332e2658a0449dab5f263790e8d58f1"],"submitter_email":["mkalwat@indianabiosciences.org","almosley@iu.edu"],"sample_protocol":[""],"repository":["MassIVE"],"file_size":["21"],"ptm_modification":["UNIMOD:21 - \"Phosphorylation.\"","UNIMOD:35 - \"Oxidation or Hydroxylation.\""],"data_protocol":[""],"omics_type":["Proteomics"],"instrument_platform":["Orbitrap Exploris 480"],"species":["Homo Sapiens (ncbitaxon:9606)","Mus Musculus (ncbitaxon:10090)"],"submitter_affiliation":["Indiana University School of Medicine","Indiana Biosciences Research Institute"],"pubmed_abstract":["β cells are dysfunctional in type 2 diabetes (T2D) and congenital hyperinsulinism (HI), but the mechanisms linking hypersecretion to β cell failure are poorly understood. Here, we use proteomics and functional assays in human and mouse β cell lines to identify VDAC1 as a target for the small molecule hypersecretion inducer SW016789. By enhancing membrane depolarization, SW016789 acutely increases Ca<sup>2+</sup> influx, eventually driving β cell dysfunction. Time-course transcriptomics analysis reveals a distinct hypersecretory response signature compared to classical endoplasmic reticulum (ER) stress, highlighting ER-associated degradation (ERAD) as a key adaptive pathway. While SW016789 reduces ERAD substrate OS-9 levels, broader ERAD component changes are limited in cell lines. However, immunostaining of the T2D human pancreas shows altered distributions of the ratios of the core ERAD components SEL1L, HRD1, and DERL3 in β cells. This work provides a detailed mechanistic characterization of a hypersecretion-specific stress response, revealing potential therapeutic targets, including VDAC1 and ERAD, for modulating β cell function and survival in disease."],"pubmed_title":["VDAC1 is a target for pharmacologically induced insulin hypersecretion in β cells."],"pubmed_authors":["Roy Gitanjali G, Ordóñez Andrea A, Binns Derk D DD, Rodrigues-Dos-Santos Karina K, Kwakye Michael B MB, King George C GC, Kuntz Rachel L RL, Mukherjee Noyonika N, Templin Andrew T AT, Tan Zhiyong Z, Richardson Timothy I TI, Doud Emma H EH, Mosley Amber L AL, Schueler Kathryn L KL, Emfinger Christopher H CH, Attie Alan D AD, Keller Mark P MP, Johnson Travis S TS, Kalwat Michael A MA"],"additional_accession":["PXD050590"]},"is_claimable":false,"name":"Target deconvolution of SW016789 in human and mouse Beta cells","description":"The target of SW016789 is unknown (PMCID: PMC9225822). This compound was identified in a high-throughput screen for insulin secretion modulators and was subsequently discovered to cause hypersecretory stress in beta cells. A photoaffinity probe was designed, Z629, based upon the structure of SW016789. Photo-crosslinking, click chemistry to biotin, and affinity purification with streptavidin-agarose was used to enrich for potential binding partners. Experiments were performed in both mouse MIN6 and human EndoC-BetaH1 beta cells. Enriched proteins were identified based on the ratio of PSMs detected in Z629 vs DMSO treatments. Candidate proteins (>2-fold) were filtered based on a >2-fold enrichment in Z629/DMSO and >1 PSM for Z629 in both MIN6 and EndoC-BetaH1. Pathway analysis indicated a role for the Vdac family of proteins which were previously identified to have an important role in Beta-cells during type 2 diabetes (PMCID: PMC6331340). Vdac1 was therefore chosen for validation studies.","dates":{"publication":"Wed Mar 13 08:39:00 GMT 2024"},"accession":"MSV000094310","cross_references":{"pubmed":["40512624"]}}