UV irradiation of Keap1 W to A mice
We discovered that the interaction of Keap1 to Cul3 is weaker than that of other KLHL proteins. The BTB domain of Keap1 has an unique Cul3-interacting region (designated C3IR) compared with the other Cul3-binding BTB domains, and replacement of this region in Keap1 with the corresponding sequence of other KLHL proteins restored stronger binding to Cul3. Evolutionary tracing suggests that Keap1 was duplicated during whole genomic duplication (WGD) in fish into Keap1A and Keap1B, each of which binds to Cul3 strongly or weakly, respectively. Keap1A was lost in reptiles and later, and Keap1B evolved into mammalian Keap1. We irradiated P3.5 neonatal mice with UV-A/B lamps with a peak of 333 nm for 4 days at 15 J/cm2/day. Whereas WT mice hardly died upon such levels of UV irradiation, ~80% of Keap1 W to A mice became lethal after 4 days of irradiation. We then performed RNA sequencing analysis with UV-irradiated mouse skin and lung.