Translational repression ofNox4mRNA via the EI24-RTRAF interaction is crucial for hydrogen peroxide homeostasis and insulin synthesis

Abstract

As a double-edged sword, the content of reactive oxygen species (ROS) is precisely controlled. Disordered actions of ROS contribute to deleterious effects, such as cancer and metabolic dysregulation associated with aging and obesity. Although it is well established that cells have developed evolutionarily conserved programs to sense and adapt to redox fluctuations, it remains unclear how to control the expression of key ROS-producing enzymes to regulate continued ROS production at healthy levels for cells such as neurons and pancreatic beta cells. These cells have weaker antioxidant defense systems but strong secretion ability. Here, we found that the endoplasmic reticulum membrane-localized protein, EI24, controls the translation of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4), which constitutively produces hydrogen peroxide (H2O2), by recruiting an RNA transcription, translation, and transport factor (RTRAF) to the 3’-UTRs ofNox4. Depletion of EI24 causes RTRAF to relocate into the nucleus, releasing the brake onNox4mRNA translation, and thus, the uncontrolled translation ofNox4leads to a substantial generation of intracellular H2O2. This suppresses the translation of V-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA), inhibits its binding to theIns2gene promoter, and ultimately hinders insulin transcription. Treatment with a specific NOX4 inhibitor or the antioxidant N-acetyl-cysteine (NAC) restoredMafAtranslation and downstream insulin synthesis while alleviating the diabetic symptoms in pancreatic beta-cell specificEi24-KO mice. In summary, our study revealed a molecular mechanism that controls the expression of NOX4, a key enzyme responsible for continuous ROS generation. This mechanism ensures low levels of H2O2and normal biological functions under physiological conditions.