NF-κB1 p50 Stabilizes HIF-1α Protein through Suppression of ATG7-dependent Autophagy

Abstract Although our previous studies revealed that NF-κB1 (p50) itself alone could initiates NF-κB transcription-independent cascades to impair protein degradation of GADD45α and C-Myc and promotes p53 protein translation upon arsenic exposure, the function and underlying mechanisms of p50 in the regulation of protein expression is much less studied because of its lacking of transactivation domain. We here discovered a novel function of p50 in its stabilization of hypoxia-inducible factor 1α (HIF-1α) protein under the condition of cells exposed to arsenic exposure. In p50 deficient (p50-/-) cells, the HIF-1α protein expression was impaired upon arsenic exposure, and such defect could be rescued by reconstitutional expression of p50. Mechanistic study revealed that the inhibition of autophagy-related gene 7 (ATG7)-dependent autophagy was in charge of p50-mediated HIF-1α protein stabilization following arsenic exposure. Moreover, p50 deletion promoted nucleolin (NCL) protein translation to enhance ATG7 mRNA transcription via directly binding transcription factor Sp1 mRNA and increase its stability. We further discovered that p50-mediated miR-494 upregulation gave rise to the inhibition of p50-mediated NCL translation by interacting with its 3’-UTR. These novel findings provide a great insight into the understanding of biomedical significance of p50 protein in arsenite-associated disease development and therapy.