LAUSR

BACKGROUND Both forkhead box O (FOXO) and nuclear factor erythroid-derived 2-like-2 (Nrf2) are key transcription factors related to stress response. While limited studies in mammals and Caenorhabditis elegans revealed interaction between FoxO/DAF-16 and Nrf2/SKN-1, the role of FOXO in metabolic detoxification and regulation of Nrf2-Keap1 signaling pathway are poorly understood in insects. RESULTS Using Tribolium castaneum as a model organism, we found that RNA interference-mediated knockdown of FOXO enhanced deltamethrin-induced lethality by affecting the mRNA levels of CYP6BQ cluster genes. We further demonstrated that injection of dsFOXO into the larvae beetles decreased expression of CncC and KEAP1 at both mRNA and protein levels. Notably, dual-luciferase assay and EMSA assay both confirmed the direct regulation of CncC by FOXO, whereas Keap1 was directly regulated by CncC. CONCLUSION FOXO can directly regulate the expression of CncC and indirectly regulate the expression of Keap1 through CncC. These data provides insights into the regulatory mechanisms of Nrf2-Keap1 signaling pathway in insects.