Author Baryshev M, Sargsyan E, Wallin G, Lejnieks A, Furudate S, Hishinuma A, Mkrtchian S.
Title Unfolded protein response is involved in the pathology of human congenital hypothyroid goiter and rat non-goitrous congenital hypothyroidism.
Journal J Mol Endocrinol
Abstract The unfolded protein response (UPR) is an intracellular signaling pathway that regulates the protein folding and processing capacity of the endoplasmic reticulum (ER). The UPR is induced by the pharmacological agents that perturb ER functions but is also activated upon excessive accumulation of the mutant secretory proteins that are unable to attain correct three-dimensional structure and are thus retained in the ER. Such defects in intracellular protein transport underlie the development of a number of phenotypically diverse inherited pathologies, termed endoplasmic reticulum storage diseases (ERSD). We have studied UPR development in two similar ERSDs, human congenital goiter caused by the C1264R and C1996S mutations in the thyroglobulin (Tg) gene and non-goitrous congenital hypothyroidism in rdw dwarf rats determined by the G2320R Tg mutation. In both cases, these mutations rendered Tg incapable of leaving the ER. A major ER chaperone immunoglobulin-binding protein (BiP), and a novel putative escort chaperone endoplasmic reticulum protein 29 KDa (ERp29) were found to be associated with Tg, which might be interpreted as the contribution of the quality control machinery to the previously shown retention of Tg in the ER. We have extended our earlier observations of ER chaperone induction with the identification of the additional ER (ERp29, ERp72, calreticulin, protein disulfide isomerase (PDI)), cytoplasmic (heat shock protein (HSP)70, HSP90) and mitochondrial (mtHSP70) upregulated chaperones and folding enzymes. Activation of the transcriptional arm of UPR, as judged by the appearance of the spliced (active) form of X-box binding protein (XBP1) and processed activating transcription factor 6 (ATF6) transcription factors was suggested to contribute to the overexpression of the ER chaperones. The processing of ATF6 was observed in both human and rat tissues with Tg mutations. Whereas, in human tissues, weak splicing of XBP1 mRNA was detected only in the C1264R mutant, all rat thyroids including wild-type contained significant amounts of the spliced form of XBP1 as opposed to human liver and rat brain tissues, implying the existence of a previously unknown tissue-specific regulation of XBP1 processing.
Volume 32(3)
Pages 903-20
Published 2004-6-1
DOI 10.1677/jme.0.0320903
PMID 15171721
MeSH Activating Transcription Factor 6 Animals Congenital Hypothyroidism* DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism Endoplasmic Reticulum / metabolism Goiter / congenital* Goiter / genetics Goiter / metabolism* Goiter / pathology Heat-Shock Proteins / metabolism Humans Hypothyroidism / genetics Hypothyroidism / metabolism* Hypothyroidism / pathology Male Molecular Chaperones / metabolism Nuclear Proteins / genetics Nuclear Proteins / metabolism Protein Conformation* Protein Folding Protein Transport / physiology Rats Rats, Inbred Strains Regulatory Factor X Transcription Factors Signal Transduction / physiology* Thyroglobulin / genetics Thyroglobulin / metabolism Thyroid Gland / metabolism Thyroid Gland / pathology Transcription Factors / genetics Transcription Factors / metabolism X-Box Binding Protein 1
IF 3.744
Times Cited 42
Rats F344.WIC-Tgrdw/Kts(strainID=1037)