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Endoplasmic reticulum (ER) stress-induced apoptosis is a primary cause and modifier of degeneration in a number of genetic disorders. Understanding how genetic variation influences the ER stress response and subsequent activation of apoptosis could improve individualized therapies and predictions of outcomes for patients. In this study, we find that the uncharacterized, membrane-bound metallopeptidase CG14516 in Drosophila melanogaster , which we rename as SUPpressor of ER stress-induced DEATH ( su ), plays a role in modifying ER stress-induced apoptosis. We demonstrate that loss of per reduces apoptosis and degeneration in the death model of ER stress through the JNK signaling cascade. This effect on apoptosis occurs without altering the activation of the unfolded protein response (IRE1 and PERK), suggesting that the beneficial prosurvival effects of this response are intact. Furthermore, we show that su per death is not only a modifier of this particular model, but affects the general tolerance to ER stress, including ER stress-induced apoptosis. Finally, we present evidence of Superdeath localization to the ER membrane. While similar in sequence to a number of human metallopeptidases found in the plasma membrane and ER membrane, its localization suggests that Rh1 G69D model of ER stress through the JNK signaling cascade. This effect on apoptosis occurs without altering the activation of the unfolded protein response (IRE1 and PERK), suggesting that the beneficial prosurvival effects of this response are intact. Furthermore, we show that su per death functions epistatically upstream of CDK5 -a known JNK-activated proapoptotic factor in this model of ER stress. We demonstrate that su per death is not only a modifier of this particular model, but affects the general tolerance to ER stress, including ER stress-induced apoptosis. Finally, we present evidence of Superdeath localization to the ER membrane. While similar in sequence to a number of human metallopeptidases found in the plasma membrane and ER membrane, its localization suggests that su per death is orthologous to ERAP1/2 in humans. Together, this study provides evidence that su per death is a link between stress in the ER and activation of cytosolic apoptotic pathways., (Copyright © 2020 by the Genetics Society of America.)

Apoptosis is the primary cause of degeneration in a number of neuronal, muscular, and metabolic disorders. These diseases are subject to a great deal of phenotypic heterogeneity in patient populations, primarily due to differences in genetic variation between individuals. This creates a barrier to effective diagnosis and treatment. Understanding how genetic variation influences apoptosis could lead to the development of new therapeutics and better personalized treatment approaches. In this study, we examine the impact of the natural genetic variation in the Drosophila Genetic Reference Panel (DGRP) on two models of apoptosis-induced retinal degeneration: overexpression of p53 or reaper ( rpr ). We identify a number of known apoptotic, neural, and developmental genes as candidate modifiers of degeneration. We also use Gene Set Enrichment Analysis (GSEA) to identify pathways that harbor genetic variation that impact these apoptosis models, including Wnt signaling, mitochondrial metabolism, and redox homeostasis. Finally, we demonstrate that many of these candidates have a functional effect on apoptosis and degeneration. These studies provide a number of avenues for modifying genes and pathways of apoptosis-related disease., (Copyright © 2019 Palu et al.)

Endoplasmic reticulum (ER) stress is an important modifier of human disease. Genetic variation in response genes is linked to inter-individual differences in the ER stress response. However, the mechanisms and pathways by which genetic modifiers are acting on the ER stress response remain unclear. In this study, we characterize the role of the long chain fatty acid elongase Baldspot (ELOVL6) in modifying the ER stress response and disease. We demonstrate that loss of Baldspot rescues degeneration and reduces IRE1 and PERK signaling and cell death in a Drosophila model of retinitis pigmentosa and ER stress (Rh1G69D). Dietary supplementation of stearate bypasses the need for Baldspot activity. Finally, we demonstrate that Baldspot regulates the ER stress response across different tissues and induction methods. Our findings suggest that ELOVL6 is a promising target in the treatment of not only retinitis pigmentosa, but a number of different ER stress-related disorders. [ABSTRACT FROM AUTHOR]