# Thyroid Hormone Receptor Mislocalization and Pathogenesis

> **NIH NIH R15** · COLLEGE OF WILLIAM AND MARY · 2022 · $425,824

## Abstract

PROJECT SUMMARY
Thyroid hormone receptors (TRs) are essential transcription factors that either activate or repress the
expression of target genes in response to thyroid hormone (T3). The proposed research explores a novel facet
of our overarching hypothesis that mislocalization of TR contributes to pathogenesis, by investigating the
molecular mechanism by which acetylation acts as a regulatory switch for TR localization. Our prior studies
supported by 2 R15 DK058028 provide a robust premise for the proposed research. Although TRs primarily
reside in the nucleus, we have shown that they shuttle rapidly between the nucleus and cytoplasm. We have
identified multiple nuclear localization signals and nuclear export signals within TR that interact with importins
and exportins, respectively, to mediate translocation into the nucleus. Our published data show that acetylation
mimetics of TR promote cytoplasmic localization of TR but at the same time enhance ligand-dependent
transcriptional activity. In contrast, mutants that mimic nonacetylated TR have reduced intranuclear mobility,
greater nuclear retention, and impaired ligand-dependent transcriptional activity. Based on these published
data and other preliminary findings, our working model implicates acetylation as a key molecular switch for
modulating TR localization, intranuclear mobility, and transcriptional activity. Here, we will address the
following unanswered questions: Is there one key acetylation site that alters nucleocytoplasmic distribution,
intranuclear mobility, and transcriptional activity? Is TR modification compartment-specific? Which
acetyltransferase(s) and deacetylase(s) regulate TR modification? Does TR acetylation affect its protein-
protein interactions, stability, or ubiquitin-mediated degradation? We will use a multi-pronged approach of
transient transfection of mammalian cells followed by quantitative fluorescence microscopy, fluorescence
recovery after photobleaching (FRAP), luciferase reporter assays, pharmacological inhibitor screening, and
coimmunoprecipitation assays, to test our model. In addition, acetylation sites will be confirmed by MS/MS
analysis, and a novel TR-based NanoBRET assay will be developed to study protein-protein interactions.
Finally, we will investigate whether mutations in TR linked to Resistance to Thyroid Hormone (RTH) syndrome
respond aberrantly to the acetylation switch, providing insight into the correlation between altered trafficking
signals in TR and endocrine disorders. Elucidating how TR acetylation is modulated will enhance
understanding of the impact this pivotal post-translational modification has upon T3 signaling. A team of
talented undergraduates will be actively engaged in the proposed research, gaining hands-on experience with
the scientific process, from project design and execution to publication and/or presentation.

## Key facts

- **NIH application ID:** 10359318
- **Project number:** 2R15DK058028-06
- **Recipient organization:** COLLEGE OF WILLIAM AND MARY
- **Principal Investigator:** Lizabeth A Allison
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $425,824
- **Award type:** 2
- **Project period:** 2001-07-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10359318

## Citation

> US National Institutes of Health, RePORTER application 10359318, Thyroid Hormone Receptor Mislocalization and Pathogenesis (2R15DK058028-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10359318. Licensed CC0.

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