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.
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.
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