A persulfidation-based mechanism controls aquaporin-8 conductance

Upon engagement of tyrosine kinase receptors, nicotinamide adenine dinucleotide phosphate (NADPH)–oxidases release H(2)O(2) in the extracellular space. We reported previously that aquaporin-8 (AQP8) transports H(2)O(2) 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 H(2)S is sufficient to block H(2)O(2) entry in unstressed cells. Silencing cystathionine β-synthase (CBS) prevents closure, suggesting that this enzyme is the main source of H(2)S. Molecular modeling indicates that C53 persulfidation displaces a nearby histidine located in the narrowest part of the channel. We propose that H(2)O(2) molecules transported through AQP8 sulfenylate C53, making it susceptible to H(2)S produced by CBS. This mechanism tunes H(2)O(2) transport and may control signaling and limit oxidative stress.