Sumoylation and localization of Nrf2 to promyelocytic leukemia nuclear bodies are involved in its degradation in the nucleus

Nrf2 (nuclear factor erythroid 2‐related factor 2) induces gene transcription by binding to the antioxidant response element(s) in target gene promoters. It is degraded primarily in the cytoplasm but can also be degraded in the nucleus. The mechanism of this nuclear degradation has not been elucidated. In HepG2 cells, we found that in the presence of the proteasome inhibitor MG‐132, GFP‐Nrf2 localized to promyelocytic leukemia nuclear bodies (PML‐NBs) in a sumoylation‐dependent manner. In vitro and in vivo sumoylation assays demonstrate that Nrf2 is sumoylated by SUMO‐1 and SUMO‐2/3. Short‐term treatment with As 2 O 3 enhances polysumoylation by SUMO‐2/3 and targets Nrf2 to PML‐NBs. Given that polysumoylation has been shown to precede ubiquitylation and subsequent degradation of at least two proteins in PML‐NBs, we explored the possibility that this mechanism may be involved in the nuclear degradation of Nrf2. Desumoylation conditions stabilize Nrf2, and a sumoylation‐deficient mutant has a longer half‐life than the wild‐type. These results implicate sumoylation and trafficking of Nrf2 to PML‐NBs in the degradation of Nrf2 in the nucleus. Supported by NIH grants # SC1CA143985 and T32HL007737