A novel crosstalk between Nrf2 and Smad2/3 bridged by two nuanced Keap1 isoforms with their divergent effects on these distinct family transcription factors

Free Radic Biol Med. 2024 Mar;213:190-207. doi: 10.1016/j.freeradbiomed.2024.01.025. Epub 2024 Jan 17.ABSTRACTThe 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 in HepG2 cells, arising from its first and another in-frame translation starting codons, respectively. In identifying those differential expression genes monitored by Keap1α and/or Keap1β, 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 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 transcriptional activity are enhanced with their prolonged half-lives and relevant signalling responses from the cytoplasmic to nuclear compartments. The activation of Smad2/3 by Keap1, Keap1α or Keap1β was much likely contributable to a coordinative or another competitive effect of Nrf2, particularly in distinct Keap1-based cellular responses to its cognate growth factor (i.e. TGF-β1) or redox stress (e.g. stimulated by tBHQ and DTT). Overall, this discover...
Source: Free Radical Biology and Medicine - Category: Biology Authors: Source Type: research