The Unfolded Protein Response (UPR) refers to intracellular signaling pathways that are activated in response to endoplasmic reticulum (ER) stress. Efficient UPR signaling can help suppress diseases caused by misfolded proteins in the ER, such as those caused by mutant rhodopsins that underlie Retinitis Pigmentosa (RP). Conversely, defective UPR can lead to the dysfunction of certain cell types that are normally under physiological ER stress. The long term goal of this project is to understand the precise role and regulatory mechanisms of UPR in eye development and retinal degeneration. The current understanding of the UPR centers around ER stress sensor proteins that include IRE1 (Inositol Requiring 1), which detects misfolded peptides through a luminal peptide binding domain and initiates a branch of UPR signaling. In this proposal, we propose experiments that may change our basic understandings of UPR and its role in eye development and disease. Specifically in Aim 1, we plan to challenge the idea that IRE1-mediated UPR?s primary physiological role is to respond to misfolded peptides in the ER. IRE1 is required for normal Drosophila eye development, but contradicting the widely accepted role of IRE1 in detecting and responding to misfolded peptides, our preliminary studies indicate that IRE1?s developmental role is independent of its luminal domain that senses misfolded peptides. Based on this, I propose plans to test the idea that IRE1?s main role in the developing eye is not to help cells respond to unfolded proteins, but instead, to respond to other sources of physiological stress.
In Aims 2 and 3, we will characterize a previously unrecognized UPR signaling branch. Specifically, we will test the hypothesis that retinoids, which are conjugated to properly folded rhodopsins to serve as chromophores, act as signaling molecules when released from misfolded rhodopsins to mediate Rhodopsin-1-specific UPR signaling. The possibility that retinoids actively regulate gene expression in Drosophila has thus far been largely overlooked. Our hypothesis is based in part on our unexpected preliminary data that retinoids can induce gene expression in Drosophila, and two such inducible genes highroad and fabp are involved in degrading mutant Drosophila Rhodopsin-1 alleles that are similar in their nature with human rhodopsin mutants that underlie RP. As part of this effort, we propose in Aim 2 to characterize the role of FABP, a Drosophila homolog of Cellular Retinoic Acid Binding Proteins, in retinoid-mediated gene expression control and retinal degeneration in the RP model.
In Aim 3, we propose to identify the transcription factor that mediates retinoid signaling in Drosophila photoreceptors, and determine its role in mutant rhodopsin degradation and retinal degeneration. A successful outcome of these plans will significantly change our current understanding of UPR?s physiological role, and may contribute to the development of therapeutic strategies against diseases of the eye.

Public Health Relevance

Unfolded Protein Response (UPR) refers to signaling pathways activated by endoplasmic reticulum (ER) stress that promote stress resistance and prevent disease. Here, I propose to identify new UPR pathways that help cells resist retinal degeneration in Drosophila models of Retinitis Pigmentosa, and to determine why UPR is required even during normal eye development.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Biology of the Visual System Study Section (BVS)
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Neuhold, Lisa
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New York University
Anatomy/Cell Biology
Schools of Medicine
New York
United States
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Huang, Huai-Wei; Brown, Brian; Chung, Jaehoon et al. (2018) highroad Is a Carboxypetidase Induced by Retinoids to Clear Mutant Rhodopsin-1 in Drosophila Retinitis Pigmentosa Models. Cell Rep 22:1384-1391
Vasudevan, Deepika; Clark, Nicholas K; Sam, Jessica et al. (2017) The GCN2-ATF4 Signaling Pathway Induces 4E-BP to Bias Translation and Boost Antimicrobial Peptide Synthesis in Response to Bacterial Infection. Cell Rep 21:2039-2047
Kang, Min-Ji; Vasudevan, Deepika; Kang, Kwonyoon et al. (2017) 4E-BP is a target of the GCN2-ATF4 pathway during Drosophila development and aging. J Cell Biol 216:115-129
Huang, Huai-Wei; Zeng, Xiaomei; Rhim, Taiyoun et al. (2017) The requirement of IRE1 and XBP1 in resolving physiological stress during Drosophila development. J Cell Sci 130:3040-3049
Ryoo, Hyung Don; Vasudevan, Deepika (2017) Two distinct nodes of translational inhibition in the Integrated Stress Response. BMB Rep 50:539-545
Vasudevan, Deepika; Ryoo, Hyung Don (2016) Detection of Cell Death in Drosophila Tissues. Methods Mol Biol 1419:131-44
Mollereau, B; Rzechorzek, N M; Roussel, B D et al. (2016) Adaptive preconditioning in neurological diseases - therapeutic insights from proteostatic perturbations. Brain Res 1648:603-616
Ryoo, Hyung Don (2016) Long and short (timeframe) of endoplasmic reticulum stress-induced cell death. FEBS J 283:3718-3722
Ryoo, Hyung Don (2015) Drosophila as a model for unfolded protein response research. BMB Rep 48:445-53
Kang, Kwonyoon; Ryoo, Hyung Don; Park, Jung-Eun et al. (2015) A Drosophila Reporter for the Translational Activation of ATF4 Marks Stressed Cells during Development. PLoS One 10:e0126795

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