Chow, C. Y. — Page 2 | bioRxiv Science

bioRxiv2019

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

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 Rh1G69D 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.\n\nSIGNIFICANCE 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.

genetics↗

bioRxiv2018

Baldspot/ELOVL6 is a conserved modifier of disease and the ER stress response

Endoplasmic reticulum (ER) stress is an important modifier of human disease. Genetic variation in genes involved in the ER stress response has been linked to inter-individual differences in this 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.\n\nAUTHOR SUMMARYDifferences in genetic background drives disease variability, even among individuals with identical, causative mutations. Identifying and understanding how genetic variation impacts disease expression could improve diagnosis and treatment of patients. Previous work has linked the endoplasmic reticulum (ER) stress response pathway to disease variability. When misfolded proteins accumulate in the ER, the ER stress response returns the cell to its normal state. Chronic ER stress leads to massive amounts of cell death and tissue degeneration. Limiting tissue loss by regulating the ER stress response has been a major focus of therapeutic development. In this study, we characterize a novel regulator of the ER stress response, the long chain fatty acid elongase Baldspot/ELOVL6. In the absence of this enzyme, cells undergoing ER stress display reduced cell death, and degeneration in a Drosophila disease model. Feeding of excess fatty acids increases degeneration to original disease levels, linking the regulatory activity of Baldspot to its enzymatic activity. Finally, we demonstrate that Baldspot can alter the ER stress response under a variety of other ER stress conditions. Our studies demonstrate that Baldspot/ELOVL6 is a ubiquitous regulator of the ER stress response and is a good candidate therapeutic target.

genetics↗