Fig. 3
Physiologic activation and regulation of NRF2 and metabolic reprogramming by NRF2 in LSCC cells. a In unstressed conditions, KEAP1 forms a ubiquitin E3 ligase complex with CULLIN3 (CUL3) and binds with NFR2 via the DLG and ETGE motifs in the Neh2 domain of NRF2 in the cytoplasm. NRF2 is then polyubiquitinated and degraded through the proteasome system after its synthesis. When cells are exposed to electrophiles or ROS, KEAP1 is modified and the KEAP1-CUL3 ubiquitin E3 ligase activity declines, which stabilizes NRF2. Stabilized and accumulated NRF2 translocates to the nucleus and functions as a transcriptional factor. NRF2 is also regulated through a KEAP1-independent mechanism in which GSK3 plays an important role. NRF2 is phosphorylated by GSK3 and then recognized by β-TrCP. By contrast, the Neh6 domain of NRF2 serves as the degron exploited in this β-TrCP-CUL1-dependent degradation of NRF2. Following its ubiquitination by the β-TrCP-CUL1 E3 ubiquitin ligase complex, NRF2 is degraded by the proteasome. b LSCC cells displayed a dual reliance on glucose and glutamine metabolism. Activation of NRF2 increases the synthesis of GSH from intracellular glutamate, cysteine, and glycine. GLS1 catalyzes the transformation of glutamine to glutamate. Cystine is imported by the xc– antiporter system (xCT). Serine and glycine are synthesized via NRF2-dependent processes. Under chronic mTOR inhibition which suppresses glycolysis, LSCC cells could upregulate glutaminolysis through the GSK3 signaling pathway which developed acquired resistance to mTOR inhibition. β-TrCP β-transducin repeat-containing protein genes, GLS1 glutaminase 1, GSH glutathione, PDK phosphoinositide-dependent kinase, ROS reactive oxygen species, TCA cycle tricarboxylic acid cycle
