Impaired inflammasome activation and bacterial clearance in G6PD deficiency due to defective NOX/p38 MAPK/AP-1 redox signaling

Yen, Wei-Chen; Wu, Yi-Hsuan; Wu, Chih-Ching; Lin, Hsin-Ru; Stern, Arnold; Chen, Shih-Hsiang; Shu, Jwu-Ching; Tsun-Yee Chiu, Daniel

Cells need to maintain redox homeostasis for regulating proper functioning. Redox pathways have been identified in and between cells for broad functions to relay and generate cellular signals. Since G6PD plays a role in the production of NADPH as the substrate of NOX, it is anticipated that G6PD may be involved in modulating redox-sensitive signaling [49] . When NADPH is decreased, superoxide production is reduced by NOX. This may cause an impaired Nrf2 antioxidant response [51] and a decrease in NF-κB [13, 52] and SP-1/HIF-1α signaling [53] [54] [55] . AP-1 signaling is a part of the G6PD-regulated redox pathway, thereby contributing to the activity of redox networks. The transcription factor AP-1 is a heterodimer composed of the proteins c-Fos, c-Jun and those from the ATF families [56] . The stability of the Jun-Fos heterodimer allows for higher DNA-binding activity [57] . G6PD knockdown decreased p38 phosphorylation and c-Fos expression, which reduced IL1B expression. The terminal differentiation of THP-1 cells is associated with the induction of c-Fos, implying that this could be the growth arrest signal in the differentiation of monocytes [58] .