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bioRxiv · 10.1101/2022.11.22.517594

A novel crosstalk between Nrf2 and Smad2/3 bridged by two nuanced Keap1 isoforms

Chen, F.·Xiao, M.·Lou, D.·Wang, Q.·Wufur, R.·Hu, S.·Zhang, Z.·Wang, Y.·Zhang, Y.
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Abstract

The Keap1-Nrf2 signalling to transcriptionally regulate antioxidant response element (ARE)-driven target genes has been accepted as key redox-sensitive pathway governing a vast variety of cellular stresses during healthy survival and disease development. Herein, we identified two nuanced isoforms and {beta} of Keap1, arising from its first and another in-frame translation starting codons, respectively. In identifying those differential expression genes monitored by Keap1 and/or Keap1{beta}, an unusual interaction of Keap1 with Smad2/3 was discovered by parsing transcriptome sequencing, Keap1-interacting protein profiling and relevant immunoprecipitation data. Further examination validated that Smad2/3 enable physical interaction with Keap1, as well as its isoforms and {beta}, by both EDGETSD and DLG motifs in the linker regions between their MH1 and MH2 domains, such that the stability of Smad2/3 and its transcriptional activity are enhanced with the prolonged half-lives and signalling responses from the cytoplasmic to nuclear compartments. The activation of Smad2/3 by Keap1, Keap1 or Keap1{beta} was likely contributable to a coordinative or another competitive effect of Nrf2, particularly in distinct Keap1-based cellular responses to its cognate growth factor or redox stress. Overall, this discovery presents a novel functional bridge crossing both the Keap1-Nrf2 redox signalling and the TGF-{beta}1-Smad2/3 pathways in healthy growth and development.

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Chen, F., Xiao, M., Lou, D., Wang, Q., Wufur, R., Hu, S., Zhang, Z., Wang, Y., Zhang, Y.. 2022-11-23. A novel crosstalk between Nrf2 and Smad2/3 bridged by two nuanced Keap1 isoforms. https://doi.org/10.1101/2022.11.22.517594

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