Determining Possible Roles of Thyroid Hormone Transporters in Non-Canonical Regulation of Thyroid Gland Function

  • While altered thyroid phenotypes can arise due to cathepsin deficiencies, functional compensation via the upregulation of cathepsin L, despite normal serum thyroid stimulating hormone (TSH) levels, in cathepsin K-deficient (Ctsk-/-) mice is unexpected. Furthermore, these mice show normal serum thyroid hormone (TH) status by increased monocarboxylate transporter Mct8-mediated TH export. Thus, alternative thyroid regulatory mechanisms that are independent of the canonical hypothalamus-pituitary-thyroid axis might exist, making Ctsk-/- mice a suitable model to study “thyroid auto-regulation”. The first part of the present study elucidates the possible roles of Mct8 and Mct10 in non-canonical regulation of cathepsin-mediated thyroglobulin (Tg) proteolysis. We assessed the thyroid phenotypes in combined cathepsin K and TH transporter deficiency, i.e., in Ctsk-/-/Mct10-/-, Ctsk-/-/Mct8-/y, and Ctsk-/-/Mct8-/y/Mct10-/- mice. Results revealed that induced lysosomal biogenesis due to autophagy, possibly triggered by thyrotoxicity, causes persistent Tg proteolysis in a counterintuitive manner in Mct8-deficient genotypes. The second part of the study examines the factors triggering autophagy in the Ctsk-/-/Mct8-/y/Mct10-/- murine model. Since Lat2 regulates autophagy in kidney and pancreas, we propose that Lat2 regulates autophagy in thyrocytes as well. Indeed, Lat2 protein amounts were significantly decreased in autophagy-induced Ctsk-/-/Mct8-/y/Mct10-/- mice. Furthermore, Lat2-/- thyroid glands showed autophagy induction and lysosomal biogenesis. The third part of this study explores whether altered TSH receptor localization can lead to differences in thyroid gland architecture. Results revealed that Mct10 deficiency results in vesicular TSH receptors as opposed to canonical basolateral TSH receptors in controls. Although altered TSH receptor localization does not result in gross alterations in thyroid gland morphology, thyrocyte survival is possibly regulated by Mct10.

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Publishing Institution:IRC-Library, Information Resource Center der Jacobs University Bremen
Granting Institution:Jacobs Univ.
Author:Vaishnavi Venugopalan
Referee:Klaudia Brix, Sebastian Springer, Heike Heuer
Advisor:Klaudia Brix
Persistent Identifier (URN):urn:nbn:de:gbv:579-opus-1010781
Document Type:PhD Thesis
Date of Successful Oral Defense:2022/03/30
Date of First Publication:2022/05/12
Academic Department:Life Sciences & Chemistry
PhD Degree:Cell Biology
Focus Area:Health
Other Countries Involved:India
Call No:2022/8

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