| Autor: |
Grieco G; Cell Biology Unit, de Duve Institute, Université catholique de Louvain, Brussels, Belgium., Janssens V; Cell Biology Unit, de Duve Institute, Université catholique de Louvain, Brussels, Belgium., Gaide Chevronnay HP; Cell Biology Unit, de Duve Institute, Université catholique de Louvain, Brussels, Belgium., N'Kuli F; Cell Biology Unit, de Duve Institute, Université catholique de Louvain, Brussels, Belgium., Van Der Smissen P; Cell Biology Unit, de Duve Institute, Université catholique de Louvain, Brussels, Belgium., Wang T; Cell Biology Unit, de Duve Institute, Université catholique de Louvain, Brussels, Belgium., Shan J; Laboratory of Developmental Biology, Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland., Vainio S; Laboratory of Developmental Biology, Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland., Bilanges B; UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6DD, UK., Jouret F; Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA), Cardiovascular Sciences, University of Liège, Liège, Belgium., Vanhaesebroeck B; UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6DD, UK., Pierreux CE; Cell Biology Unit, de Duve Institute, Université catholique de Louvain, Brussels, Belgium. christophe.pierreux@uclouvain.be., Courtoy PJ; Cell Biology Unit, de Duve Institute, Université catholique de Louvain, Brussels, Belgium. |
| Abstrakt: |
Kidney proximal tubular cells (PTCs) are highly specialized for ultrafiltrate reabsorption and serve as paradigm of apical epithelial differentiation. Vps34/PI3-kinase type III (PI3KC3) regulates endosomal dynamics, macroautophagy and lysosomal function. However, its in vivo role in PTCs has not been evaluated. Conditional deletion of Vps34/PI3KC3 in PTCs by Pax8-Cre resulted in early (P7) PTC dysfunction, manifested by Fanconi-like syndrome, followed by kidney failure (P14) and death. By confocal microscopy, Vps34 ∆/∆ PTCs showed preserved apico-basal specification (brush border, NHERF-1 versus Na + /K + -ATPase, ankyrin-G) but basal redistribution of late-endosomes/lysosomes (LAMP-1) and mis-localization to lysosomes of apical recycling endocytic receptors (megalin, cubilin) and apical non-recycling solute carriers (NaPi-IIa, SGLT-2). Defective endocytosis was confirmed by Texas-red-ovalbumin tracing and reduced albumin content. Disruption of Rab-11 and perinuclear galectin-3 compartments suggested mechanistic clues for defective receptor recycling and apical biosynthetic trafficking. p62-dependent autophagy was triggered yet abortive (p62 co-localization with LC3 but not LAMP-1) and PTCs became vacuolated. Impaired lysosomal positioning and blocked autophagy are known causes of cell stress. Thus, early trafficking defects show that Vps34 is a key in vivo component of molecular machineries governing apical vesicular trafficking, thus absorptive function in PTCs. Functional defects underline the essential role of Vps34 for PTC homeostasis and kidney survival. |
