Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2022.11.22.517594v1?rss=1

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

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. Those common and specific genes monitored by Keap1 and/or Keap1{beta} were unravelled by transcriptomic sequencing of indicated experimental cell lines. Amongst them, an unusual interaction of Keap1 with Smad2/3 was discovered by parsing transcriptome sequencing, protein profiling, and immunoprecipitation data. Further examinations 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 responsiveness from the cytoplasmic to nuclear compartments. Such activation of Smad2/3 by Keap1, Keap1 or Keap1{beta} was contributable to a competitively inhibitory effect of Nrf2. Overall, this discovery presents a novel functional bridge crossing the Keap1-Nrf2 and the TGF-{beta}1-Smad2/3 signalling pathways in healthy growth and development.

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