CNC/NRF oxidative and xenobiotic stress response

A cross-species module for the oxidative and xenobiotic stress response driven by cap'n'collar (CNC) basic-leucine-zipper transcription factors: NRF2 (NFE2L2) in vertebrates, CncC in Drosophila and SKN-1 in Caenorhabditis elegans. In unstressed cells the CNC factor is kept scarce by constitutive cullin-RING ubiquitin ligase-dependent degradation, and its nuclear activity is further restrained by glycogen synthase kinase-3 (GSK-3) phosphorylation. Two degradation arms are known. In vertebrates and insects the BTB-Kelch protein KEAP1 binds the CNC factor and presents it to a CUL3-RING ligase, and reactive KEAP1 cysteines act as sensors whose modification by oxidants and electrophiles stops degradation. Nematodes have no KEAP1; there the WD40 protein WDR-23, the ortholog of human DCAF11, restrains SKN-1 together with the CUL-4/DDB-1 (CRL4) ligase, and DCAF11 also targets human NRF2 for degradation through a separate degron. Stress-activated kinases promote nuclear accumulation of the factor; in C. elegans the NSY-1/SEK-1/PMK-1 p38 MAPK cascade phosphorylates SKN-1. Nuclear CNC factors then induce a phase II detoxification program that includes glutamate-cysteine ligase, the rate-limiting enzyme of glutathione synthesis, and glutathione S-transferases, and loss of the CNC factor makes animals sensitive to oxidative stress. NRF2 binds antioxidant response elements as a heterodimer with small MAF proteins, whereas SKN-1 binds DNA as a monomer through its Skn domain.

History. This module was first written as a concrete C. elegans SKN-1 module and was generalized to the CNC/NRF response across bilaterians. All nematode evidence is retained; the nematode-specific wiring is kept as one variant of the degradation step and as the nematode-characterized p38 input part. Boundary. The module covers the stress-inducible CNC response: constitutive ligase-dependent degradation of the CNC factor, GSK-3 inhibitory phosphorylation, stress-activated kinase input, CNC transcription, and two representative phase II enzyme outputs. Outside the boundary are the developmental role of maternal SKN-1 in EMS blastomere specification, the ER-associated NRF1/SKN-1A proteasome-recovery response (a separate CNC paralog program), SKN-1B in ASI neurons for dietary-restriction longevity, and the KEAP1-sequestering autophagy receptor SQSTM1/p62. The C. elegans insulin/IGF-1-like AKT-1/AKT-2/SGK-1 inhibitory input (PMID:18358814) and, in mammals, PI3K/AKT inhibition of GSK3B are recorded as context. The GATA factor ELT-3 is a SKN-1 co-activator for gst-4 and BRAP-2 restrains the p38 input (PMID:28600327); both are context, not members. Small MAF partners of NRF2 are not modeled as a part because SKN-1 acts without them. Context taxon. Bilateria is used because the stress response with this regulatory architecture is documented in nematodes (SKN-1), arthropods (Drosophila Keap1/CncC, PMID:18194654) and vertebrates (KEAP1/NRF2). The CNC transcription factor itself is older: its PAINT node PTN002399572 (PTHR24411) is placed at Eumetazoa, so cnidarian CNC proteins exist, but their deployment in an oxidative stress response is not established in the cached evidence. Degradation lineages. KEAP1 is present in vertebrates and insects but absent from C. elegans; WDR-23/DCAF11 and CRL4 occupy the nematode position. This is an analogy of role, not of sequence; KEAP1 binds the Neh2 ETGE/DLG motifs of NRF2, whereas DCAF11 binds the distinct Neh2 DIDLID sequence (PMID:31586112), so mammals use both arms at once (ONE_OR_MORE). No KEAP1-like cysteine-sensor step is known for WDR-23. Drosophila Keap1 and CncC have no gene review and are cited only as literature evidence. Human CUL4A and CUL4B have no gene review, so the CUL4 scaffold role is grounded only on worm CUL-4. In mammals GSK3B phosphorylation of the NRF2 Neh6 domain creates a degron for the beta-TrCP (BTRC)-CUL1 ligase (Reactome R-HSA-9762094, R-HSA-9762093); BTRC has no gene review, so this third degradation route is recorded here rather than as a variant. In C. elegans the reported GSK-3 readout is nuclear exclusion. Activating kinases. The NSY-1/SEK-1/PMK-1 cascade is shared with intestinal antibacterial immunity, where PMK-1 acts through ATF-7 and other targets. The cascade itself is modeled in MODULE:c_elegans_pmk1_intestinal_immunity, which is the place for kinase-relay detail, and the taxon-neutral MODULE:p38_cascade gives the generic relay. Here the cascade is one optional input part, marked as characterized in nematodes, because a conserved p38 phosphorylation of vertebrate NRF2 is not established in the cached evidence. Grounding caveats. The wdr-23 review is filed on S6FN32, a 498-residue product that lacks the N termini of the experimentally studied cytoplasmic WDR-23A and nuclear WDR-23B isoforms (both from P90794); its review keeps the broader molecular adaptor activity (GO:0060090), of which the ubiquitin-like ligase-substrate adaptor activity used here for the family role (GO:1990756, from the human DCAF11 review) is a descendant. The worm ddb-1 review assigns ubiquitin ligase complex scaffold activity (GO:0160072), as does the first core function of the human DDB1 review, and that term is used for the DDB1 role. Ubiquitination of SKN-1 by CUL-4/DDB-1/WDR-23 has not been shown biochemically in the cached literature; the 2009 study states it as presumed. The protective role of GCS-1 is clearest for arsenite (PMID:16333752).