AQP8, a redoxtat controlling tyrosine kinase signalling

AQP8-mediated H2O2 transport allows efficient amplification of tyrosine kinase signalling, therefore influencing pathways frequently dysregulated under tumour progression. Besides, control of H2O2 cell permeability impacts life-death cell decisions in response to stress. Despite the important consequences of AQP8 gating, the precise biochemical modification that inhibits H2O2 transport still remains to be identified. We show here that the mechanism of regulation implies sulphydration of AQP8. Addition of an exogenous H2S donor (NaHS) is sufficient to block H2O2 entry and dampen EGF receptor signalling, bypassing stress. Moreover, cells expressing non-inhibitable AQP8 mutant (e.g. C53S) are able to transport H2O2 also upon H2S treatment. Stress-induced blockade of transport requires cystathionine-beta-synthase, a key enzyme in the transulphuration pathway. These findings identify a novel circuit modulating the strength and duration of key signalling pathways based on AQP8 regulation by sulphydration.