Exquisite sensitivity of Polycystin-1 to H2O2 concentration in the endoplasmic reticulum
Year: 2024
Type: article
Abstract: Aquaporin11 (AQP11) is an endoplasmic reticulum (ER) resident peroxiporin. It allows H 2 O 2 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 (H 2 O 2 ) 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 H 2 O 2 intra and inter-organellar fluxes, with important implications in the pathogenesis and onset of PKD. • Increased (H 2 O 2 ) ER upon AQP11 KD impacts PC-1 biogenesis at different levels. • Lowering (H 2 O 2 ) ER by targeted catalase expression rescues PC-1 processing. • PC-1 biogenesis is exquisitely sensitive to the ER redox environment.
Source: Redox Biology
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,900
Awards: G2323569667, G2473566682, G742218021
OpenAlex ID: W4405963077