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)...
Saved in:
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-03-01
|
| Series: | Redox Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231724004646 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850190102927507456 |
|---|---|
| author | Elisa Speranza Ilaria Sorrentino Alessandra Boletta Roberto Sitia |
| author_facet | Elisa Speranza Ilaria Sorrentino Alessandra Boletta Roberto Sitia |
| author_sort | Elisa Speranza |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-d711ed28fd7844d2a91d47f028f1159f |
| institution | OA Journals |
| issn | 2213-2317 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj-art-d711ed28fd7844d2a91d47f028f1159f2025-08-20T02:15:24ZengElsevierRedox Biology2213-23172025-03-018010348610.1016/j.redox.2024.103486Exquisite sensitivity of Polycystin-1 to H2O2 concentration in the endoplasmic reticulumElisa Speranza0Ilaria Sorrentino1Alessandra Boletta2Roberto Sitia3Division of Genetics and Cell Biology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, 20132, Milan, Italy; Università Vita-Salute San Raffaele, 20132, Milan, ItalyDivision of Genetics and Cell Biology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, 20132, Milan, Italy; Università Vita-Salute San Raffaele, 20132, Milan, ItalyDivision of Genetics and Cell Biology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, 20132, Milan, ItalyDivision of Genetics and Cell Biology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, 20132, Milan, Italy; Università Vita-Salute San Raffaele, 20132, Milan, Italy; Corresponding author. Division of Genetics and Cell Biology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, 20132, Milan, Italy.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.http://www.sciencedirect.com/science/article/pii/S2213231724004646Aquaporin 11H2O2Polycystin-1Polycystic kidney diseaseProtein transportRedox homeostasis |
| spellingShingle | Elisa Speranza Ilaria Sorrentino Alessandra Boletta Roberto Sitia Exquisite sensitivity of Polycystin-1 to H2O2 concentration in the endoplasmic reticulum Redox Biology Aquaporin 11 H2O2 Polycystin-1 Polycystic kidney disease Protein transport Redox homeostasis |
| title | Exquisite sensitivity of Polycystin-1 to H2O2 concentration in the endoplasmic reticulum |
| title_full | Exquisite sensitivity of Polycystin-1 to H2O2 concentration in the endoplasmic reticulum |
| title_fullStr | Exquisite sensitivity of Polycystin-1 to H2O2 concentration in the endoplasmic reticulum |
| title_full_unstemmed | Exquisite sensitivity of Polycystin-1 to H2O2 concentration in the endoplasmic reticulum |
| title_short | Exquisite sensitivity of Polycystin-1 to H2O2 concentration in the endoplasmic reticulum |
| title_sort | exquisite sensitivity of polycystin 1 to h2o2 concentration in the endoplasmic reticulum |
| topic | Aquaporin 11 H2O2 Polycystin-1 Polycystic kidney disease Protein transport Redox homeostasis |
| url | http://www.sciencedirect.com/science/article/pii/S2213231724004646 |
| work_keys_str_mv | AT elisasperanza exquisitesensitivityofpolycystin1toh2o2concentrationintheendoplasmicreticulum AT ilariasorrentino exquisitesensitivityofpolycystin1toh2o2concentrationintheendoplasmicreticulum AT alessandraboletta exquisitesensitivityofpolycystin1toh2o2concentrationintheendoplasmicreticulum AT robertositia exquisitesensitivityofpolycystin1toh2o2concentrationintheendoplasmicreticulum |