Alisa Beyzin
Pronouns: she/her
Research Mentor(s): Xiaohan Zhang
Research Mentor School/College/Department: Internal Medicine / Medicine
Program:
Authors: Alisa Beyzin, Xiaohan Zhang, Peter Arvan
Session: Session 7: 4:40 pm – 5:30 pm
Poster: 18
Abstract
Hypothyroidism – an insufficiency in thyroid hormones – is the most common thyroid disorder. Multiple thyroid specific proteins are essential for thyroid hormone synthesis, including thyroglobulin (Tg), thyroid peroxidase (TPO), and sodium ion symporter (NIS), which are transcriptionally regulated by thyroid stimulating hormone (TSH). The endoplasmic reticulum (ER) provides the infrastructure necessary for the synthesis and folding of these proteins. To maintain the critical environment that’s important for proper protein folding and processing in the ER, specific molecular chaperones are highly expressed, one of the most abundant ER molecular chaperones being Grp170. To better understand the role of this molecular chaperone in thyroid hormone synthesis, an inducible, thyrocyte-specific GRP170-KO mouse has been generated. We find that adult mice with loss of thyrocyte Grp170 have a decrease of serum T4 level in the blood, with an increase of the circulating TSH level, which is consistent with primary hypothyroidism. The thyrocyte-specific Grp170 deficiency mice have a comparable expression of Tg and TPO, whereas thyroidal T4 within Tg molecules is much diminished, associated with altered expression of NIS. Interestingly, the thyroid histology of GRP170-KO mice shows a relatively hypoactive state, which does not reflect its high serum TSH level. Further analysis revealed that Grp170 affects the trafficking and expression of TSH receptor (TSHR) in the GRP170-KO thyroid, suggesting an impaired TSH signaling. GRP170 knockdown in vitro with siRNA transfection results in TSHR misfolding and decreased TSHR trafficking to the cell surface. Overall, our work suggests that Grp170 facilitates the folding and trafficking of TSHR; loss of Grp170 impairs thyroid hormones synthesis via a collective effect of NIS and TSH signaling.
