A persulfidation-based mechanism controls aquaporin-8 conductance.

Abstract

Upon engagement of tyrosine kinase receptors, nicotinamide adenine dinucleotide phosphate (NADPH)-oxidases release H₂O₂ in the extracellular space. We reported previously that aquaporin-8 (AQP8) transports H₂O₂ across the plasma membrane and is reversibly gated during cell stress, modulating signal strength and duration. We show that AQP8 gating is mediated by persulfidation of cysteine 53 (C53). Treatment with H₂S is sufficient to block H₂O₂ entry in unstressed cells. Silencing cystathionine β-synthase (CBS) prevents closure, suggesting that this enzyme is the main source of H₂S. Molecular modeling indicates that C53 persulfidation displaces a nearby histidine located in the narrowest part of the channel. We propose that H₂O₂ molecules transported through AQP8 sulfenylate C53, making it susceptible to H₂S produced by CBS. This mechanism tunes H₂O₂ transport and may control signaling and limit oxidative stress.