# Defining the cytoplasmic sequestration of Caenorhabditis elegans orphan nuclear receptor 49 on trafficking vesicles

> **NIH NIH F31** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $33,394

## Abstract

PROJECT SUMMARY
Nuclear hormone receptors are ligand-gated transcription factors that primarily reside in the nucleus.
Upon ligand binding, nuclear hormone receptors bind to DNA and initiate elaborate transcriptional
responses involved in sexual differentiation, hormonal regulation, metabolic control and other biological
processes specific to metazoans. Nuclear receptors are considered one of the most ancestral receptors
that are hypothesized to have aided in the development of multicellular organisms, yet half of all known
nuclear hormone receptors do not have defined endogenous ligands. These receptors are referred to
as orphan nuclear receptors. Hepatic Nuclear Factor 4 (HNF4) is an orphan receptor, and it is involved
in diseases such as Type 1 Diabetes, Fanconi Renotubular Syndrome 4, Type-2 Diabetes (non-insulin
dependent), hyperinsulinemia, and multiple types of cancer. My preliminary studies have elucidated a
single Caenorhabditis elegans nuclear hormone receptor, NHR-49, a functional ortholog to HNF4, that
is sequestered in the cytosol. A small percentage of receptors have been reported in the cytosol,
including the glucocorticoid receptor, which is sequestered in the cytosol through direct interactions
with molecular chaperone HSP90. Upon ligand binding, the glucocorticoid receptor dissociates from
HSP90 and translocates to the nucleus to initiate transcription. In an opposing manner, I hypothesize
that an endogenous fatty acid, geranylgeranyl, sequesters NHR-49 in the cytosol through binding it to
trafficking vesicles. When intracellular carbon levels are low, the geranylgeranyl moiety is no longer
synthesized. This in turn, abolishes the inhibitory sequestration of NHR-49 to cytosolic trafficking
vesicle, promotes nuclear localization, and induces transcriptional upregulation of genes to re-establish
homeostatic vesicular trafficking. Therefore, the central hypothesis of this proposal is that one of the
two covalently linked geranylgeranyl moieties on RAB-11.1(a recycling endosomal protein) is bound to
NHR-49, while the other geranylgeranyl tethers the RAB-11.1/NHR-49 complex to the trafficking
vesicle. To test this hypothesis, I will use multiple transgenic C. elegans strains that are fluorescently
labeled for different ablated forms of NHR-49 and RAB-11.1. Experiments proposed in Aim 1 will define
the structural boundaries of NHR-49’s subcellular localization and vesicular association. Aim 2 will
identify the endogenous ligand sequestering NHR-49 in the cytoplasm. Additionally, 13% of
commercially available drugs target the 50% of human nuclear receptors that have been deorphanized.
NHR-49’s mammalian ortholog, HNF4, has been studied time and time again without identification of a
sole endogenous ligand responsible for its transcriptional activity. The identification of a post-
translational modification as an endogenous ligand for NHR-49 provides potential translatability to the
HNF4, which is responsible for a myriad of lipid metab...

## Key facts

- **NIH application ID:** 10466793
- **Project number:** 5F31GM140620-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Lexus Marc Tatge
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $33,394
- **Award type:** 5
- **Project period:** 2021-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10466793

## Citation

> US National Institutes of Health, RePORTER application 10466793, Defining the cytoplasmic sequestration of Caenorhabditis elegans orphan nuclear receptor 49 on trafficking vesicles (5F31GM140620-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10466793. Licensed CC0.

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