The Drosophila metallopeptidase superdeath decouples apoptosis from the activation of the ER stress response

Abstract

Endoplasmic reticulum (ER) stress-induced apoptosis is a primary cause and modifier of degeneration in a number of genetic disorders. Understanding how genetic variation between individuals 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 (superdeath), plays a role in modifying ER stress-induced apoptosis. We demonstrate that loss of superdeath reduces apoptosis and degeneration in the 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 pro-survival effects of this response are intact. Furthermore, we show that superdeath functions epistatically upstream of CDK5, a known JNK-activated pro-apoptotic factor in this model of ER stress. We demonstrate that superdeath is not only a modifier of this particular model, but functions as a general modifier of ER stress-induced apoptosis across different tissues and ER stresses. Finally, we present evidence of Superdeath localization to the endoplasmic reticulum membrane. While similar in sequence to a number of human metallopeptidases found in the plasma membrane and ER membrane, its localization suggests that superdeath is orthologous to ERAP1/2 in humans.Together, this study provides evidence that superdeath is a link between stress in the ER and activation of cytosolic apoptotic pathways. KEYWORDS ER stress, apoptosis, metallopeptidase, modifier genes SIGNIFICANCE STATEMENTGenetic diseases display a great deal of variability in presentation, progression, and overall outcomes. Much of this variability is caused by differences in genetic background among patients.One process that commonly modifies degenerative disease is the endoplasmic reticulum (ER) stress response. Understanding the genetic sources of variation in the ER stress response could improve individual diagnosis and treatment decisions. In this study, we characterized one such modifier in Drosophila melanogaster, the membrane-bound metallopeptidase CG14516 (superdeath). Loss of this enzyme suppresses a model of ER stress-induced degeneration by reducing cell death without altering the beneficial activation of the unfolded protein response. Our findings make superdeath and its orthologues attractive therapeutic targets in degenerative disease.

Natural Genetic Variation Screen inDrosophilaIdentifies Wnt Signaling, Mitochondrial Metabolism, and Redox Homeostasis Genes as Modifiers of Apoptosis

“…Ultimately, our goal is not to treat these associations as definitive, but to use these variants to nominate candidate modifier genes or pathways for subsequent functional validation. Despite the weak signals, this approach has been used to successfully identify bona fide modifier genes in previous work (Chow et al 2013, 2015, 2016; Palu and Chow 2018, 2019; Lavoy et al 2018; Ahlers et al 2019). Here again, this genome-wide association analysis yields a number of genes that potentially underlie the variable expressivity of degenerative phenotypes induced by these models of apoptosis.…”