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

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 Jan 17:S0891-5849(24)00025-X. doi: 10.1016/j.freeradbiomed.2024.01.025.
Feilong Chen 1,  Qing Wang 1,  Mei Xiao 2,  Deshuai Lou 3,  Reziyamu Wufur 1,  Shaofan Hu 2,  Zhengwen Zhang 4,  Yeqi Wang 5,  Yiguo Zhang 6
Affiliations

Affiliations

  • 1 College of Bioengineering and Graduate School, Chongqing University, No. 174 Shazheng Street, Shapingba District, Chongqing 40044, China; Chongqing University Jiangjin Hospital, School of Medicine, Chongqing University, No. 725 Jiangzhou Avenue, Dingshan Street, Jiangjin District, Chongqing 402262, China; The Laboratory of Cell Biochemistry and Topogenetic Regulation, College of Bioengineering and Faculty of Medical Sciences, Chongqing University, No. 174 Shazheng Street, Shapingba District, Chongqing 40044, China.
  • 2 College of Bioengineering and Graduate School, Chongqing University, No. 174 Shazheng Street, Shapingba District, Chongqing 40044, China; The Laboratory of Cell Biochemistry and Topogenetic Regulation, College of Bioengineering and Faculty of Medical Sciences, Chongqing University, No. 174 Shazheng Street, Shapingba District, Chongqing 40044, China.
  • 3 Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing 400067, China.
  • 4 Laboratory of Neuroscience, Institute of Cognitive Neuroscience and School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, England, United Kingdom.
  • 5 College of Bioengineering and Graduate School, Chongqing University, No. 174 Shazheng Street, Shapingba District, Chongqing 40044, China.
  • 6 Chongqing University Jiangjin Hospital, School of Medicine, Chongqing University, No. 725 Jiangzhou Avenue, Dingshan Street, Jiangjin District, Chongqing 402262, China; The Laboratory of Cell Biochemistry and Topogenetic Regulation, College of Bioengineering and Faculty of Medical Sciences, Chongqing University, No. 174 Shazheng Street, Shapingba District, Chongqing 40044, China. Electronic address: yiguozhang@cqu.edu.cn.
PMID: 38242246 DOI: 10.1016/j.freeradbiomed.2024.01.025
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 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 its 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 discovery presents a novel functional bridge crossing the Keap1-Nrf2 redox signalling and the TGF-β1-Smad2/3 pathways so as to coordinately regulate the healthy growth and development.

Keywords

Keap1; Keap1α; Keap1β; Nrf2; Protein-protein interaction; Smad2; Smad3; Transcriptional regulation.

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