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

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 α and β of Keap1, arising from its first and another in-frame translation starting codons, respectively. Those common and specific genes monitored by Keap1α and/or Keap1β 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 α and β, 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, Keap1α or Keap1β was contributable to a competitively inhibitory effect of Nrf2. Overall, this discovery presents a novel functional bridge crossing the Keap1-Nrf2 and the TGF-β1-Smad2/3 signalling pathways in healthy growth and development.