Exquisite sensitivity of Polycystin-1 to H₂O₂ concentration in the endoplasmic reticulum

Aquaporin11 (AQP11) is an endoplasmic reticulum (ER) resident peroxiporin. It allows H₂O₂ transport from the lumen to the cytosol, guaranteeing redox homeostasis and signaling in and between the two organelles. Interestingly, Aqp11^-/- mice develop a fatal, early onset polycystic kidney disease (PKD) similar to Autosomal Dominant PKD, a condition frequently associated with mutations of polycystin-1 (PC-1) in human patients. Here we investigated the molecular mechanisms of AQP11-associated PKD. Using different cell models, we show that transient downregulation of AQP11 selectively prevents the biogenesis of overexpressed PC-1. Expression of catalase in the ER lumen rescues the phenotype, demonstrating a direct role of (H₂O₂)_ER in controlling the complex maturation of PC-1. Analysis of endogenous Pc-1 revealed an additional regulatory role at the pre-translational level. Taken together, our results show that AQP11 controls the complex biogenesis of PC-1 at multiple levels governing H₂O₂ intra and inter-organellar fluxes, with important implications in the pathogenesis and onset of PKD.