MAPK-directed activation of the whitefly transcription factor CREB leads to P450-mediated imidacloprid resistance

Xin Yang, Shun Deng, Xuegao Wei, Jing Yang, Qiannan Zhao, Cheng Yin, Tianhua Du, Zhaojiang Guo, Jixing Xia, Zezhong Yang, Wen Xie, Shaoli Wang, Qingjun Wu, Fengshan Yang, Xuguo Zhou, Ralf Nauen, Chris Bass, Youjun Zhang

Research output: Contribution to journalArticlepeer-review

108 Scopus citations


The evolution of insect resistance to pesticides poses a continuing threat to agriculture and human health. While much is known about the proximate molecular and biochemical mechanisms that confer resistance, far less is known about the regulation of the specific genes/gene families involved, particularly by trans-acting factors such as signal-regulated transcription factors. Here we resolve in fine detail the trans-regulation of CYP6CM1, a cytochrome P450 that confers resistance to neonicotinoid insecticides in the whitefly Bemisia tabaci, by the mitogen-activated protein kinase (MAPK)-directed activation of the transcription factor cAMPresponse element binding protein (CREB). Reporter gene assays were used to identify the putative promoter of CYP6CM1, but no consistent polymorphisms were observed in the promoter of a resistant strain of B. tabaci (imidacloprid-resistant, IMR), which overexpresses this gene, compared to a susceptible strain (imidaclopridsusceptible, IMS). Investigation of potential trans-acting factors using in vitro and in vivo assays demonstrated that the bZIP transcription factor CREB directly regulates CYP6CM1 expression by binding to a cAMP-response element (CRE)-like site in the promoter of this gene. CREB is overexpressed in the IMR strain, and inhibitor, luciferase, and RNA interference assays revealed that a signaling pathway of MAPKs mediates the activation of CREB, and thus the increased expression of CYP6CM1, by phosphorylation-mediated signal transduction. Collectively, these results provide mechanistic insights into the regulation of xenobiotic responses in insects and implicate both the MAPK-signaling pathway and a transcription factor in the development of pesticide resistance.

Original languageEnglish
Pages (from-to)10246-10253
Number of pages8
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number19
StatePublished - May 12 2020

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. We thank Murad Ghanim (The Volcani Center) and Prof. Xiaoqiang Yu (University of Missouri, Kansas City) for suggestions that improved the paper. This research was supported by the National Natural Science Foundation of China (grants 31420103919 and 31601664); National Key R&D Program of China (grant 2016YFD0200500); China Agriculture Research System (CARS-24-C-02); the Beijing Key Laboratory for Pest Control and Sustainable Cultivation of Vegetables; and the Science and Technology Innovation Program of the Chinese Academy of Agricultural Sciences (CAAS-ASTIP-IVFCAAS). C.B. received funding from the European Research Council under the European Union’s Horizon 2020 Research and Innovation Programme (grant 646625).

Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.


  • CREB
  • Cytochrome P450
  • Insecticide resistance
  • MAPK
  • Neonicotinoid insecticide

ASJC Scopus subject areas

  • General


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