Buli Fu, Jinjin Liang, Jinyu Hu, Tianhua Du, Qimei Tan, Chao He, Xuegao Wei, Peipan Gong, Jing Yang, 

Shaonan Liu, Mingjiao Huang, Lianyou Gui, Kui Liu, Xuguo Zhou, Ralf Nauen, Chris Bass, 

Xin Yang, and Youjun Zhang

PNAS, July 3, 2024; 121 (28) e2402407121

Significance

The molecular basis for evolutionary gain and loss remains elusive. Here, we report that a G protein-coupled receptor (GPCR) triggered mitogen-activated protein kinase (MAPK) signaling cascades trans -regulates a key P450 gene CYP6CM1 by activating a transcription factor (TF) cAMP-response element binding protein (CREB), contributing to insecticide resistance. However, this same signaling pathway also negatively modulates three key oogenesis genes Ex, Va, and Bg via recruiting another TF CncC, which leads to reproductive cost. We further find a positive feedback loop between the MAPK p38 and GPCR NPFF2 that continuously activates the MAPK pathways, thereby promoting resistance evolution but with a strong reproductive cost. Thus, our results resolve in fine detail the pleiotropic role of GPCR–MAPK signaling cascades in evolutionary trade-offs.

Abstract

Trade-offs between evolutionary gain and loss are prevalent in nature, yet their genetic basis is not well resolved. The evolution of insect resistance to insecticide is often associated with strong fitness costs; however, how the fitness trade-offs operates remains poorly understood. Here, we show that the mitogen-activated protein kinase (MAPK) pathway and its upstream and downstream actors underlie the fitness trade-offs associated with insecticide resistance in the whitefly Bemisia tabaci. Specifically, we find a key cytochrome P450 gene CYP6CM1, that confers neonicotinoids resistance to in B. tabaci, is regulated by the MAPKs p38 and ERK through their activation of the transcription factor cAMP-response element binding protein. However, phosphorylation of p38 and ERK also leads to the activation of the transcription repressor Cap “n” collar isoform C (CncC) that negatively regulates exuperantia (Ex), vasa (Va), and benign gonial cell neoplasm (Bg), key genes involved in oogenesis, leading to abnormal ovary growth and a reduction in female fecundity. We further demonstrate that the transmembrane G protein-coupled receptor (GPCR) neuropeptide FF receptor 2 (NPFF2) triggers the p38 and ERK pathways via phosphorylation. Additionally, a positive feedback loop between p38 and NPFF2 leads to the continuous activation of the MAPK pathways, thereby constitutively promoting neonicotinoids resistance but with a significant reproductive cost. Collectively, these findings provide fundamental insights into the role of cis-trans regulatory networks incurred by GPCR–MAPK signaling pathways in evolutionary trade-offs and applied knowledge that can inform the development of strategies for the sustainable pest control.

See https://www.pnas.org/doi/10.1073/pnas.2402407121

Figure 6: A proposed working model for GPCR–MAPK signaling cascades underlying trade-offs between insecticide resistance and reproductive costs. Exposure to neonicotinoids (NCS) is detected by the GPCR NPFF2 that then initiates the MAPK signaling pathway by phosphorylation. MAPK p38 and ERK not only activate the TF CREB contributing to overexpression of CYP6CM1 that confers resistance to neonicotinoids but also recruit another TF CncC that negatively regulates Ex, Va, and Bg leading to abnormal ovary growth and reduced fecundity. Notably, a positive feedback loop mediated by p38 triggers the phosphorylation of NPFF2, which in turn continuously activates the MAPK pathways, thereby promoting resistance evolution but with strong reproductive cost.