ER-tethered RNA-binding protein controls NADPH oxidase translation for hydrogen peroxide homeostasis

Hydrogen peroxide (H₂O₂) functions as a signaling molecule in diverse cellular processes. While cells have evolved the capability to detect and manage changes in H₂O₂ levels, the mechanisms regulating key H₂O₂-producing enzymes to maintain optimal levels, especially in pancreatic beta cells with notably weak antioxidative defense, remain unclear. We found that the protein EI24 responds to changes in H₂O₂ concentration and regulates the production of H₂O₂ by controlling the translation of NOX4, an enzyme that is constitutively active, achieved by recruiting an RNA-binding protein, RTRAF, to the 3'-UTR of Nox4. Depleting EI24 results in RTRAF relocating into the nucleus, releasing the brake on NOX4 translation. The excessive production of H₂O₂ by liberated NOX4 further suppresses the translation of the key transcription factor MafA, ultimately preventing its binding to the Ins2 gene promoter and subsequent transcription of insulin. Treatment with a specific NOX4 inhibitor or the antioxidant NAC reversed these effects and alleviated the diabetic symptoms in beta-cell specific Ei24-KO mice. This study revealed a new mechanism through which cells regulate oxidative stress at the translational level, involving an ER-tethered RNA-binding protein that controls the expression of the key H₂O₂-producing enzyme NOX4.