Thyroglobulin Interactome Profiling Defines Altered Proteostasis Topology Associated With Thyroid Dyshormonogenesis
| العنوان: | Thyroglobulin Interactome Profiling Defines Altered Proteostasis Topology Associated With Thyroid Dyshormonogenesis |
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| المؤلفون: | Madison T. Wright, Logan Kouba, Lars Plate |
| المصدر: | Molecular & Cellular Proteomics : MCP |
| بيانات النشر: | Elsevier BV, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Proteomics, DSP, dithiobis(succinimidyl propionate), GRP94, 94 kDa glucose regulated protein, affinity purification - mass spectrometry, STT3B, oligosaccharyl transferase complex catalytic subunit B, medicine.medical_treatment, Hsp90, heat shock protein 90, protein-protein interactions, Gene mutation, T3, Triiodothyronine, Biochemistry, Interactome, ERAD, ER-associated degradation, Analytical Chemistry, N-glycosylation, asparagine-linked protein glycosylation, OST, oligosaccharyl transferase complex, UPR, unfolded protein response, GANAB, glucosidase II alpha subunit, Tandem Mass Spectrometry, ChEL, cholinesterase-like domain, protein folding, UGGT1, UDP-glucose glycoprotein glucosyltansferase 1, TMT, tandem mass tags, Protein Interaction Maps, PDIA6, protein disulfide isomerase family A member 6, EndoH, endoglycosidase H, OS-9, OS9 endoplasmic reticulum lectin, 0303 health sciences, biology, Chemistry, 030302 biochemistry & molecular biology, congenital hypothyroidism, BiP, binding immunoglobulin protein, cell secretion, Cell biology, tandem mass tags, DNAJB11, DnaJ heat shock protein family member B11, SEL1L, SEL1L adaptor subunit of ERAD E3 ubiquitin ligase, Oligosaccharyltransferase complex, CANX, calnexin, DNAJC10, DnaJ heat shock protein family member C10, MAN1B1, mannosidase alpha class 1B member 1, EDEM, ER degradation enhancing alpha-mannosidase, PDIA4, protein disulfide isomerase family A member 4, Endoplasmic-reticulum-associated protein degradation, Thyroglobulin, FOXRED2, RAD-dependent oxidoreductase domain containing 2, Cell Line, ER, endoplasmic reticulum, 03 medical and health sciences, CHX, cycloheximide, Calnexin, T4, thyroxine, medicine, Humans, protein quality control, PQC, protein quality control, PDIA3, protein disulfide isomerase family A member 3, Molecular Biology, CH, congenital hypothyroidism, GO, gene ontology, 030304 developmental biology, Research, CALR, calreticulin, Hsp70/40, heat shock protein 70 kDa and 40 kDa chaperone/co-chaperone system, PN, proteostasis network, Tg, thyroglobulin, Proteostasis, STT3A, oligosaccharyl transferase complex catalytic subunit A, Chaperone (protein), Mutation, biology.protein |
| الوصف: | Thyroglobulin (Tg) is a secreted iodoglycoprotein serving as the precursor for triiodothyronine and thyroxine hormones. Many characterized Tg gene mutations produce secretion-defective variants resulting in congenital hypothyroidism. Tg processing and secretion is controlled by extensive interactions with chaperone, trafficking, and degradation factors comprising the secretory proteostasis network. While dependencies on individual proteostasis network components are known, the integration of proteostasis pathways mediating Tg protein quality control and the molecular basis of mutant Tg misprocessing remain poorly understood. We employ a multiplexed quantitative affinity purification–mass spectrometry approach to define the Tg proteostasis interactome and changes between WT and several congenital hypothyroidism variants. Mutant Tg processing is associated with common imbalances in proteostasis engagement including increased chaperoning, oxidative folding, and engagement by targeting factors for endoplasmic reticulum–associated degradation. Furthermore, we reveal mutation-specific changes in engagement with N-glycosylation components, suggesting distinct requirements for 1 Tg variant on dual engagement of both oligosaccharyltransferase complex isoforms for degradation. Modulating dysregulated proteostasis components and pathways may serve as a therapeutic strategy to restore Tg secretion and thyroid hormone biosynthesis. Graphical Abstract Highlights • Quantitative multiplexed affinity purification—mass spectrometry was used to map the comprehensive thyroglobulin interactome. • Tg interactome consist of a diverse set of protein quality control components. • Mutants share imbalances with folding, disulfide processing, and degradation elements. • N-glycosylation plays a key role in the degradation of mutant thyroglobulin. In Brief Congenital hypothyroidism can result from mutations in the thyroglobulin (Tg) gene impairing protein secretion of the defective Tg variants. The molecular basis of mutant Tg misprocessing has remained poorly understood. Here we map the Tg interactome and quantify mutation specific changes in protein–protein interactions between Tg and protein quality control components. By integrating interactions across protein quality control pathways, we highlight shared imbalances in protein folding, disulfide processing, and degradation, and reveal mutant-specific roles for N-glycosylation in Tg processing. |
| تدمد: | 1535-9476 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7d17fb4f57923b89d5f68b68711a933eTest https://doi.org/10.1074/mcp.ra120.002168Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....7d17fb4f57923b89d5f68b68711a933e |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15359476 |
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