Role of Gα₁₂ and Gα₁₃ as novel switches for the activity of Nrf2, a key antioxidative transcription factor

Gα₁₂ and Gα₁₃ function as molecular regulators responding to extracellular stimuli. NF-E2-related factor 2 (Nrf2) is involved in a protective adaptive response to oxidative stress. This study investigated the regulation of Nrf2 by Gα₁₂ and Gα₁₃. A deficiency of Gα₁₂, but not of Gα₁₃, enhanced Nrf2 activity and target gene transactivation in embryo fibroblasts. In mice, Gα₁₂ knockout activated Nrf2 and thereby facilitated heme catabolism to bilirubin and its glucuronosyl conjugations. An oligonucleotide microarray demonstrated the transactivation of Nrf2 target genes by Gα₁₂ gene knockout. Gα₁₂ deficiency reduced Jun N-terminal protein kinase (JNK)-dependent Nrf2 ubiquitination required for proteasomal degradation, and so did Gα₁₃ deficiency. The absence of Gα₁₂, but not of Gα₁₃, increased protein kinase C δ (PKC δ) activation and the PKC δ-mediated serine phosphorylation of Nrf2. Gα₁₃ gene knockout or knockdown abrogated the Nrf2 phosphorylation induced by Gα₁₂ deficiency, suggesting that relief from Gα₁₂ repression leads to the Gα₁₃- mediated activation of Nrf2. Constitutive activation of Gα₁₃ promoted Nrf2 activity and target gene induction via Rho-mediated PKC δ activation, corroborating positive regulation by Gα₁₃. In summary, Gα₁₂ and Gα₁₃ transmit a JNK-dependent signal for Nrf2 ubiquitination, whereas Gα₁₃ regulates Rho-PKC δ-mediated Nrf2 phosphorylation, which is negatively balanced by Gα₁₂.