PXD017724

PXD017724 is an original dataset announced via ProteomeXchange.

Title	Cell survival and adaptation to chronic endoplasmic reticulum stress in thyrocytes
Description	The large secretory glycoprotein, thyroglobulin, is the primary translation product of thyroid follicular cells. This difficult-to-fold protein is readily susceptible to structural alterations that render the misfolded thyroglobulin unable to be exported from the endoplasmic reticulum (ER) a known cause of congenital hypothyroidism, with severe, chronic thyrocyte ER stress. Nevertheless, patients with this disease commonly grow a goiter indicative of thyroid cell survival and adaptation. To model this, we have treated PCCl3 thyrocytes with continuous exposure to tunicamcyin (causing an ER stress that can be specifically attributed to thyroglobulin misfolding). In response, PCCl3 cells escape by downregulating expression of Mfsd2a (the tunicamycin transporter). By contrast, following CRISPR/Cas9-mediated deletion of Mfsd2a, PCCl3 cells cannot escape the continuous, chronic effects of high-dose tunicamycin (as demonstrated by persistent accumulation of unglycosylated thyroglobulin); nevertheless the thyrocytes live and grow. A comprehensive proteomic analysis of these cells adapted to chronic ER protein misfolding reveals many hundreds of up-regulated proteins, supporting stimulation of ER chaperones, oxidoreductases, and stress responses as well as lipid biosynthesis pathways. Further, we noted: a) increased phospho-AMP-kinase-B (suggesting upregulated AMPK activity) and decreased phospho-S6 and protein translation (suggesting decreased mTOR activity), consistent with conserved cell survival/adaptation pathways; and b) a suggestion of less differentiated thyrocyte phenotype with decreased PAX8, FOXE1, and TPO protein, as well as a significant decrease of thyroglobulin mRNA levels.
HostingRepository	MassIVE
AnnounceDate	2020-04-10
AnnouncementXML	Submission_2020-04-10_08:04:27.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Nick Carruthers
SpeciesList	scientific name: Homo sapiens; common name: human; NCBI TaxID: 9606;
ModificationList	L-methionine sulfoxide
Instrument	Orbitrap Fusion ETD

Revision	Datetime	Status	ChangeLog Entry
0	2020-02-25 07:30:22	ID requested
⏵ 1	2020-04-10 08:04:28	announced

Morishita Y, Kabil O, Young KZ, Kellogg AP, Chang A, Arvan P, Thyrocyte cell survival and adaptation to chronic endoplasmic reticulum stress due to misfolded thyroglobulin. J Biol Chem, 295(20):6876-6887(2020) [pubmed]

submitter keyword: thyroid, thyroglobulin, glycoprotein, misfolding, secretory pathway, ER stress, proteomics

Peter Arvan
contact affiliation	University of Michigan
contact email	parvan@umich.edu
lab head
Nick Carruthers
contact affiliation	Wayne State U
contact email	carruthers@wayne.edu
dataset submitter

MassIVE dataset URI

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