The physiological unfolded protein response in the thyroid epithelial cells

Area of Science:

• Cellular Biology
• Endocrinology
• Molecular Biology

Background:

• Endoplasmic reticulum (ER) homeostasis is crucial for cellular function.
• Perturbations in ER homeostasis trigger the unfolded protein response (UPR).
• UPR is an adaptive cellular reaction to stress, involving specific signaling pathways.

Purpose of the Study:

• To investigate the activation of UPR under physiological conditions.
• To examine UPR activation during hormone-stimulated thyroglobulin (Tg) expression in thyroid cells.
• To compare physiological UPR with drug-induced UPR.

Main Methods:

• Hormone stimulation of thyroid cells to induce thyroglobulin (Tg) synthesis.
• Analysis of UPR activation through ATF6, PERK, and IRE1 pathways.
• Detection of UPR target gene expression, including ER molecular chaperones.
• Assessment of spliced mRNA for transcription factor XBP1 as an indicator of IRE1 activation.

Main Results:

• Hormone stimulation led to early increase in Tg synthesis within 1 hour.
• UPR activation was observed, evidenced by ATF6 and PERK pathway engagement.
• ER molecular chaperones, UPR target genes, were subsequently expressed.
• Minimal IRE1 activation was detected, indicated by the absence of spliced XBP1 mRNA.

Conclusions:

• Physiological UPR is activated during hormone-stimulated Tg synthesis in differentiating thyrocytes.
• This physiological UPR exhibits weaker manifestation compared to drug-induced stress.
• Distinct patterns of UPR sensor activation (ATF6/PERK dominant, IRE1 minimal) characterize physiological UPR.