NRH:Quinone Oxidoreductase 2 (NQO2) Protein Competes with the 20 S Proteasome to Stabilize Transcription Factor CCAAT Enhancer-binding Protein α (C/EBPα), Leading to Protection against γ Radiation-induced Myeloproliferative Disease

Background: NQO2 protects against radiation-induced myeloproliferative disease, but the mechanism remains unknown. Results: Radiation-induced NQO2, independent of NQO1, competes with the 20 S proteasome for interaction with C/EBP region Ser-268 to Val-279 to stabilize C/EBP, leading to protection against myeloproliferative disease. Conclusion: NQO2 stabilizes C/EBP against 20 S degradation to protect against myeloproliferative disease. Significance: Stress-responsive NQO2 functions as an endogenous factor against myeloproliferative diseases. NRH:quinone oxidoreductase 2 (NQO2) is a flavoprotein that protects cells against radiation and chemical-induced oxidative stress. Disruption of the NQO2 gene in mice leads to radiation-induced myeloproliferative diseases. In this report, we showed that the 20 S proteasome and NQO2 both interact with myeloid differentiation factor CCAAT-enhancer-binding protein (C/EBP). The interaction of the 20 S proteasome with C/EBP led to the degradation of C/EBP. NQO2, in the presence of its cofactor NRH, protected C/EBP against 20 S degradation. Deletion and site-directed mutagenesis demonstrated that NQO2 and 20 S competed for the same binding region of S(268)GAGAGKAKKSV(279) in C/EBP. Exposure of mice and HL-60 cells to radiation enhanced the levels of NQO2, which led to an increased NQO2 interaction with C/EBP and decreased 20 S interaction with C/EBP. NQO2 stabilization of C/EBP was independent of NQO1, even though both interacted with the same C/EBP domain. NQO2(-/-) mice, deficient in NQO2, failed to stabilize C/EBP. This contributed to the development of radiation-induced myeloproliferative disease in NQO2(-/-) mice.