Protein Disulfide Isomerase Modulates the Activation of Thyroid Hormone Receptors

Abstract

Thyroid hormone receptors (TRs) are responsible for mediating thyroid hormone (T3 and T4) actions at a cellular level. They belong to the nuclear receptor (NR) superfamily and execute their main functions inside the cell nuclei as hormone-regulated transcription factors. These receptors also exhibit so-called “non-classic” actions, for which other cellular proteins, apart from coregulators inside nuclei, regulate their activity. Aiming to find alternative pathways of TR modulation, we searched for interacting proteins and found that PDIA1 interacts with TRβ in a yeast two-hybrid screening assay. The functional implications of PDIA1—TR interactions are still unclear; however, our co-immunoprecipitation (co-IP) and fluorescence assay results showed that PDI was able to bind both TR isoforms in vitro. Moreover, T3 appears to have no important role in these interactions in cellular assays, where PDIA1 was able to regulate transcription of TRα and TRβ-mediated genes in different ways depending on the promoter region and on the TR isoform involved. Although PDIA1 appears to act as a coregulator, it binds to a TR surface that does not interfere with coactivator binding. However, the TR:PDIA1 complex affinity and activation are different depending on the TR isoform. Such differences may reflect the structural organization of the PDIA1:TR complex, as shown by models depicting an interaction interface with exposed cysteines from both proteins, suggesting that PDIA1 might modulate TR by its thiol reductase/isomerase activity.

Protein disulfide isomerase A1‑associated pathways in the development of stratified breast cancer therapies

“…These effects in the ERα-positive cells are mediated possibly through the physical interaction between PDIA1 and the ERα and the regulation of the transcriptional activity of the receptor (26) whereas the impact of the PDIA1 in the ERα-negative cells is mediated through estrogen-independent pathways. To solidify our previous observations indicating the differential PDIA1 effects in a type and genetic background tumor-dependent mode (4) and taking into account the fact that PDIA1 exerts these differential effects functioning as a transcriptional co-modulator (27,33,54) in the PDIA1-silenced MCF-7 cells was higher compared to that identified in the MDA-MB-231 cells suggesting that the main effects of PDIA1 on gene expression were mediated by the activity of the ERα transcription factor whereas in the TNBC cells through other transcription factors associated with PDIA1 such as hypoxia-inducible factor 1α (HIF-1α) (18), nuclear factor (erythroid-derived 2)-like 2 (NRF2) (32) and nuclear factor (NF)-κB activity (27).…”

Comparative Proteomic and Metabolomic Analysis of Human Osteoblasts, Differentiated from Dental Pulp Stem Cells, Hinted Crucial Signaling Pathways Promoting Osteogenesis

“…They include thyroid and parathyroid hormones, estrogens, growth hormones, and 1,25-dihydroxyvitamin D3. Thyroid-stimulating hormone (TSH) works via TSH receptors, which are activated by protein disulfide isomerase [ 80 ]. Additionally, TSH affects secondary messengers (for example, Ca 2+ signaling cascade through IP3) in extrathyroidal tissues.…”

A discovery-based proteomics approach identifies protein disulfide isomerase (PDIA1) as a biomarker of β cell stress in type 1 diabetes

“…In addition to its intracellular role as a thiol reductase (31,42,43), PDIA1 is known to be a secreted protein (31). At present, circulating biomarkers that reflect the health of the β cell are lacking.…”