title: Detrimental effects of proteasome inhibition activity in Drosophila melanogaster: implication of ER stress, autophagy, and apoptosis.
abstract: In eukaryotes, the ubiquitin-proteasome machinery regulates a number of fundamental cellular processes through accurate and tightly controlled protein degradation pathways. We have, herein, examined the effects of proteasome functional disruption in Dmp53                 (+/+) (wild-type) and Dmp53                 (-/-)                 Drosophila melanogaster fly strains through utilization of Bortezomib, a proteasome-specific inhibitor. We report that proteasome inhibition drastically shortens fly life-span and impairs climbing performance, while it also causes larval lethality and activates developmentally irregular cell death programs during oogenesis. Interestingly, Dmp53 gene seems to play a role in fly longevity and climbing ability. Moreover, Bortezomib proved to induce endoplasmic reticulum (ER) stress that was able to result in the engagement of unfolded protein response (UPR) signaling pathway, as respectively indicated by fly Xbp1 activation and Ref(2)P-containing protein aggregate formation. Larva salivary gland and adult brain both underwent strong ER stress in response to Bortezomib, thus underscoring the detrimental role of proteasome inhibition in larval development and brain function. We also propose that the observed upregulation of autophagy operates as a protective mechanism to "counterbalance" Bortezomib-induced systemic toxicity, which is tightly associated, besides ER stress, with activation of apoptosis, mainly mediated by functional Drice caspase and deregulated dAkt kinase. The reduced life-span of exposed to Bortezomib flies overexpressing Atg1_RNAi or Atg18_RNAi supports the protective nature of autophagy against proteasome inhibition-induced stress. Our data reveal the in vivo significance of proteasome functional integrity as a major defensive system against cellular toxicity likely occurring during critical biological processes and morphogenetic courses.
authors.affiliation: Department of Cell Biology and Biophysics, University of Athens, Panepistimiopolis, Zografou, Athens, Greece. panosvel@biol.uoa.gr
authors.forename: Panagiotis D
authors.initials: PD
authors.lastname: Velentzas
authors.forename: Athanassios D
authors.initials: AD
authors.lastname: Velentzas
authors.forename: Vassiliki E
authors.initials: VE
authors.lastname: Mpakou
authors.forename: Marianna H
authors.initials: MH
authors.lastname: Antonelou
authors.forename: Lukas H
authors.initials: LH
authors.lastname: Margaritis
authors.forename: Issidora S
authors.initials: IS
authors.lastname: Papassideri
authors.forename: Dimitrios J
authors.initials: DJ
authors.lastname: Stravopodis
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D001522:Behavior, Animal / Q000187:drug effects; D001897:Boronic Acids / Q000633:toxicity*; D000069286:Bortezomib; D004331:Drosophila melanogaster / Q000187:drug effects* / Q000201:enzymology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000502:physiology; D005260:Female; D053208:Kaplan-Meier Estimate; D007814:Larva / Q000187:drug effects / Q000254:growth & development; D008136:Longevity / Q000187:drug effects; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D006080:Ovarian Follicle / Q000187:drug effects / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000633:toxicity*; D011719:Pyrazines / Q000633:toxicity*; D015996:Survival Rate
chemical_list: D001897:Boronic Acids; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex