Anti-apoptotic and anti-oxidative effects of DDX24 through HO-1 transcriptional regulation

DEAD-box helicase 24 (DDX24) is a member of the DEAD-box protein family, which is essential for various aspects of RNA metabolism. DDX24 has been reported to play a role in ribosome biogenesis, transcription, and mRNA stability. Previous studies have implicated the functions of DDX24 in innate immunity, vascular malformation, cell growth, and cancer progression. Here, we describe a novel function of DDX24 in regulating the oxidative stress response and protecting cells from apoptosis. Our research revealed that DDX24 specifically regulates the expression of the heme oxygenase-1 (HO-1) gene, as determined by RNA sequencing analysis. HO-1 is responsible for degrading heme into carbon monoxide (CO), biliverdin, and ferrous ion (Fe2+), thereby exerting anti-apoptotic and anti-oxidative effects. We validated the regulation of HO-1 by DDX24 in both DDX24-depleted and DDX24-overexpressing HEK293 cells. Our findings indicate that DDX24 is involved in the induction of HO-1 expression under oxidative stress conditions. Importantly, DDX24 regulates the transcription of HO-1 instead of its mRNA stability, likely acting at the promoter and enhancer E1 region of the HO-1 gene. Furthermore, DDX24 depletion in HEK293T cells inhibits cell viability. DDX24 exerts both anti-apoptotic and anti-oxidative effects during oxidative stress. These results suggest that DDX24 plays a crucial role in protecting cells from oxidative stress-induced damage by regulating the transcription of HO-1.

DEAD盒解旋酶24（DEAD-box helicase 24，DDX24）属于DEAD盒蛋白家族，在RNA代谢的多个关键环节中发挥不可或缺的作用。已有研究证实，DDX24参与核糖体生物发生、转录调控以及mRNA稳定性维持。既往研究还揭示了DDX24在固有免疫、血管畸形、细胞生长及癌症进展中的重要功能。本研究首次报道了DDX24在调控氧化应激反应、保护细胞免受凋亡损伤中的全新功能。通过RNA测序分析，我们发现DDX24可特异性调控血红素氧合酶1（heme oxygenase-1，HO-1）的基因表达。HO-1可将血红素降解为一氧化碳（carbon monoxide，CO）、胆绿素与亚铁离子（ferrous ion，Fe²+），从而发挥抗凋亡与抗氧化效应。我们分别在DDX24敲低与DDX24过表达的HEK293细胞中验证了DDX24对HO-1的调控作用。研究结果显示，在氧化应激条件下，DDX24参与HO-1表达的诱导过程。值得注意的是，DDX24通过结合HO-1基因的启动子与增强子E1区域，直接调控HO-1的转录而非影响其mRNA稳定性。此外，在HEK293T细胞中敲低DDX24会抑制细胞活力。在氧化应激过程中，DDX24同时具备抗凋亡与抗氧化的保护作用。上述结果表明，DDX24可通过调控HO-1的转录，在保护细胞免受氧化应激诱导的损伤中发挥关键作用。