ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: J Biol Chem. 2020;295:6876–6887.

In this experimental study, Morishita et al. developed a CRISPR/Cas-9 mediated cell model to investigate the molecular effects of thyroglobulin (TG) accumulation in the endoplasmatic reticulum (ER) of thyrocytes, as is observed in the context of dyshormonogenic CH caused by TG gene mutations. TG accumulation in the ER is a result of TG mutations altering the three-dimensional structure of the large TG glycoprotein dimer. Under normal conditions TG is proteolyzed in lysosomes and does not accumulate in the ER. First, the authors showed, that thyrocytes survive and grow in the presence of chronic ER stress. Secondly, the authors revealed that thyrocytes adapted to chronic ER stress. Proteomic analysis of their chronic ER stress model provided important insights into several active molecular mechanisms. The major finding was up-regulated AMP-Kinase activity and down-regulated mTOR activity, which is a conserved cell survival mechanism promoting adaptation to ER stress. A second key mechanism to escape chronic ER stress was a less differentiated thyrocyte phenotype with decreased protein levels of thyrocyte differentiation markers such as FOXE1, PAX8 and TPO.

In summary, these extensive in vitro data are in accordance with the phenotype of patients with TG mutations and of mice models of TG accumulation and provide fascinating new insights into the molecular mechanisms associated with misfolded TG in human TG mutation associated CH. Whether mutations in the hormonogenic tyrosine residues in the TG dimer (see first paper of this chapter, [1]) cause similar effects remains to be shown.

Reference:

1. Coscia F, Taler-Verčič A, Chang VT, Sinn L, O’Reilly FJ, Izoré T, Renko M, Berger I, Rappsilber J, Turk D, Löwe J. The structure of human thyroglobulin. Nature. 2020;578:627–630.