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Fig. 4 | Molecular Neurodegeneration

Fig. 4

From: Impaired antioxidant KEAP1-NRF2 system in amyotrophic lateral sclerosis: NRF2 activation as a potential therapeutic strategy

Fig. 4

Schematic model of the KEAP1-NRF2 signalling pathway under basal conditions (a), OS (b), and after the recovery of cellular redox homeostasis (c). (a) Under basal conditions NRF2 is sequestered by the KEAP1-NEDD8-CUL3-RBX1 complex in the cytoplasm, transferring ubiquitin (Ub) proteins from E2 ligase to the Neh2 domain in NRF2. In addition, the UBX7-p97-UFD1/NPL4 complex interacts with ubiquitinated NRF2 and NEDD8-CUL3 complex and transfers NRF2 to 26S proteasome for its degradation. (b) OS causes the oxidation of cysteine residues in KEAP1, inducing a conformational change in its structure and preventing NRF2 ubiquitination. NRF2 is therefore stabilized and translocates to the nucleus, where it binds to sMaf proteins activating ARE-driven genes. (c) Upon the recovery of redox homeostasis, KEAP1 translocates into the nucleus and induces NRF2 nuclear export. In the cytosol, NRF2 is ubiquitinated and degraded, and its level returns to be physiologically low

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Molecular Neurodegeneration

ISSN: 1750-1326