Transcriptional stress responses induced by compartment-targeted misfolding-prone proteins in Drosophila

Loss of proteostasis is an aging hallmark and the culprit of many age-related diseases. Different cell compartments experience distinctive challenges to maintain protein quality control but it remains underexplored how subcellular proteostasis is regulated by aging. Here, by targeting the misfolding_x0002_prone FlucDM luciferase to the cytoplasm, mitochondria, and nucleus, we have established transgenic sensors to examine subcellular proteostasis in Drosophila. Analysis of detergent-insoluble and -soluble levels of compartment-targeted FlucDM variants indicates that thermal stress, cold shock, and endocrine signaling differentially affect subcellular proteostasis during aging. Moreover, aggregation-prone proteins that cause different neurodegenerative diseases induce a diverse range of outcomes on FlucDM insolubility, suggesting that subcellular proteostasis is deranged in a disease-specific manner. Further analyses with FlucDM and mass spectrometry indicate that pathogenic tauV337M regulates in opposite manners the solubility of protein sets located in distinct organelles. Altogether, compartment-targeted FlucDM variants pinpoint a diverse modulation of subcellular proteostasis by aging regulators. Overall design: RNA-sequencing data from Drosophila melanogaster strains (whole flies, males, 10-days-old) reared at 18C, 25, and 29C, and that express misfolding-prone proteins localized primarily to the cytoplasm (Cyto-FlucDM), the mitochondria (Mito-FlucDM), and the nucleus (NLS-FlucDM) were compared to isogenic control flies (w1118) that do not express FlucDM.