Thyroglobulin Interactome Profiling Defines Altered Proteostasis Topology Associated With Thyroid Dyshormonogenesis.
affinity purification - mass spectrometry
cell secretion
congenital hypothyroidism
protein folding
protein quality control
protein-protein interactions
tandem mass tags
Journal
Molecular & cellular proteomics : MCP
ISSN: 1535-9484
Titre abrégé: Mol Cell Proteomics
Pays: United States
ID NLM: 101125647
Informations de publication
Date de publication:
2021
2021
Historique:
received:
14
06
2020
revised:
15
10
2020
accepted:
18
11
2020
pubmed:
14
2
2021
medline:
15
3
2022
entrez:
13
2
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33581410
pii: S1535-9476(20)35122-7
doi: 10.1074/mcp.RA120.002168
pmc: PMC7950113
pii:
doi:
Substances chimiques
TG protein, human
0
Thyroglobulin
9010-34-8
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
100008Subventions
Organisme : NIGMS NIH HHS
ID : R35 GM133552
Pays : United States
Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Conflict of interest Authors declare no competing interests.
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