# Unfolded Protein Response in Drosophila models of Retinitis Pigmentosa

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2022 · $423,750

## Abstract

Project Summary
Rhodopsins are G-protein coupled proteins that initiate the visual signal transduction cascade in response to
light exposure. The mechanism of Rhodopsin homeostasis draws research interest in part because
dysfunctional Rhodopsins are among the most frequent causes of Retinitis Pigmentosa (RP), a genetic disorder
with age-related retinal degeneration. Among those associated with RP are Rhodopsin mutants with impaired
protein folding properties. Rhodopsin undergoes synthesis and folding in the endoplasmic reticulum (ER), and
excessive misfolding of Rhodopsin could impose stress on this organelle. In response to ER stress, cells
activate an adaptive signaling response that regulates gene expression, widely referred to as the Unfolded
Protein Response (UPR). Among others, UPR signaling induces the expression of genes that help to fold or
degrade misfolded proteins in the ER. One of the UPR signaling branches is mediated by the ER stress sensor
PERK and its downstream effector ATF4. The basic mechanisms of UPR signaling, Rh1 homeostasis, and
retinal degeneration are conserved in Drosophila melanogaster. Specifically, Drosophila ninaE encodes the
Rhodopsin-1 (Rh1) protein expressed in adult eye photoreceptors. A mutant allele of this gene, ninaEG69D,
serves as a model for RP as it imposes ER stress, activates the UPR, and dominantly causes age-related
retinal degeneration. The long-term goal of this project is to harness the genetic and genomic tools of
Drosophila to understand the role of UPR in retinal degeneration. Our preliminary studies based on this
approach suggest a need to significantly revise our conventional view of the UPR in retinal degeneration. In
Specific Aims 1 and 2, I propose to re-evaluate the idea that ATF4 is the primary downstream effector of
PERK-mediated UPR. Arguing against this conventional notion, we recently found that a bZIP transcription
factor Xrp1 mediates ATF4-independent PERK signaling. We will determine how Xrp1 is regulated during UPR,
and how they affect retinal degeneration in the Drosophila RP model. In addition, we plan to test the idea that
the C/EBP family transcription factor IRBP18 works together with Xrp1 to mediate the UPR in the Drosophila RP
model. We further propose to identify the human equivalent of the Xrp1/IRBP18 complex. In Aim 3, I propose to
investigate how Rh1 is degraded in the Drosophila models of RP. Until now, there has been much focus on the
ubiquitin ligases at the ER that can help degrade misfolded proteins. Unexpectedly, our photoreceptor-specific
gene expression profiling studies reveal that many endosomal trafficking regulators are induced in ninaEG69D/+
photoreceptors. Based on this, we plan to test whether these endosomal factors mediate the degradation of
Rh1 in these photoreceptors. We further propose to test if this newly found ER stress-endosome link affects the
course of retinal degeneration in this RP model. A successful outcome of these plans may help significa...

## Key facts

- **NIH application ID:** 10520255
- **Project number:** 2R01EY020866-12
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** HYUNG D RYOO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $423,750
- **Award type:** 2
- **Project period:** 2010-08-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10520255

## Citation

> US National Institutes of Health, RePORTER application 10520255, Unfolded Protein Response in Drosophila models of Retinitis Pigmentosa (2R01EY020866-12). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10520255. Licensed CC0.

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