The Role of Sulfhydryl Reactivity of Small Molecules for the Activation of the KEAP1/NRF2 Pathway and the Heat Shock Response
Figure 1
The KEAP1/NRF2 pathway and the heat shock response are highly inducible essential defense systems that allow the cell to adapt and survive under various conditions of stress by regulating the expression of elaborate networks of several hundred genes with versatile cytoprotective functions. At low concentrations (a), inducers (yellow stars) bind to cysteine residues of the protein sensor KEAP1 (purple). Consequently, KEAP1 loses its ability to target transcription factor NRF2 (red) for ubiquitination via CUL3 (cyan)-dependent E3 ubiquitin ligase, preventing subsequent proteosomal degradation of NRF2 and allowing its accumulation, nuclear translocation, and binding to the ARE as a heterodimer with a small MAF protein (not shown) to induce expression of NRF2-target genes. At high concentrations (b), in addition to activating the KEAP1/NRF2 pathway, inducers also activate the heat shock response by chemically reacting with transcription factor HSF1 (green), or a negative regulator of HSF1, such as Hsp90 (pink) or Hsp70 (not shown). As a result, HSF1 dissociates from the protein complex, trimerizes, undergoes complex posttranslational modifications, translocates to the nucleus, and induces expression of HSF1-target genes.
