Inhibiting the proteasome reduces molecular and biological impacts of the natural product insecticide, spinosad. Issue 8 (5th February 2021)

• Record Type: Journal Article
• Authors: Nguyen, Joseph; Ghazali, Razi; Batterham, Philip; Perry, Trent
• Is Part Of: Pest management science. Volume 77:Issue 8(2021)
• Page Start: 3777
• Page End: 3786
• Publication Date: 2021-02-05
• Subjects: insecticide resistance -- spinosad -- nicotinic acetylcholine receptor -- proteasome; Pests -- Control -- Periodicals; Pesticides -- Periodicals; 632.9
• DOI: 10.1002/ps.6290
• Languages: English
• ISSNs: 1526-498X

Abstract

Abstract: BACKGROUND: Insecticide targets are often identified by mutations that confer resistance, but the intricacies of insecticide binding and downstream processes leading to insect death often remain obscure. Mutations in α6‐like nicotinic acetylcholine receptor subunit genes have been associated with high levels of resistance to spinosad in many insect species, including Drosophila melanogaster . Here, we aimed to expand our understanding of the effects of the natural product insecticide spinosad on its protein target, the α6 subunit, using genetic tools available in D. melanogaster . RESULTS: Functional, fluorescently tagged Dα6 subunits (Dα6 YFP ) were developed to allow observation of the protein in vivo . Larvae expressing Dα6 YFP were exposed to a sub‐lethal concentration of spinosyn A (0.025 ppm) for 6 days, leading to a 64% reduction in fluorescence relative to unexposed larvae. Direct application of high doses of spinosyn A to dissected larval brains resulted in a visible 38.25% decrease in Dα6 YFP within 20 min, indicating that degradation of the Dα6 protein occurred in response to spinosyn A exposure. Chemical inhibition of the proteasome system using the multiple myeloma treatment drug, PS‐341 reduced loss of Dα6 YFP in response to spinosyn A at the 20‐min time point to 6.35%. In addition, in vivo administration of PS‐341 prior to spinosad exposure reduced the effect of spinosad on larval activity. CONCLUSION: Based on these data, we propose that exposure to spinosad leads to degradation of the α6‐like target protein, a potentially novel element in the mode of action of spinosyns that may contribute to their toxicity towards insects. © 2021 Society of Chemical Industry Abstract : Fluorescently tagged nicotinic acetylcholine receptor subunits reveal that spinosad exposure leads to degradation of Dα6. Chemically inhibiting this degradation reduces the effects of spinosad, indicating potential involvement in spinosad's mode of action.