Aquaporin-8 (AQP8) allows the bidirectional transport of water and hydrogen peroxide across biological membranes. Depending on its concentration, H2O2 exerts opposite roles, amplifying growth factor signalling in physiological conditions but causing severe cell damage when in excess. Thus, H2O2 permeability is likely to be tightly controlled in living cells. Aims: In this study, we investigated whether and how the transport of H2O2 through plasma membrane AQP8 is regulated, particularly during cell stress. Results: We show that diverse cellular stress conditions, including heat, hypoxia and ER stress, reversibly inhibit the permeability of AQP8 to H2O2 and water. Preventing the accumulation of intracellular reactive oxygen species (ROS) during stress counteracts AQP8 blockade. Once inhibition is established, AQP8-dependent transport can be rescued by reducing agents. Neither H2O2 and water transport are impaired in stressed cells expressing a mutant AQP8 in which cysteine 53 had been replaced by serine. Cells expressing this mutant are more resistant to stress-, drug- and radiation-induced growth arrest and death. Innovation and conclusion: The control of AQP8-mediated H2O2 transport provides a novel mechanism to regulate cell signalling and survival during stress.
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