Abstract
Mutations in the gene NPHS2 are the most common cause of hereditary steroid-resistant nephrotic syndrome. Its gene product, the stomatin family member protein podocin represents a core component of the slit diaphragm, a unique structure that bridges the space between adjacent podocyte foot processes in the kidney glomerulus. Dislocation and misexpression of slit diaphragm components have been described in the pathogenesis of acquired and hereditary nephrotic syndrome. However, little is known about mechanisms regulating cellular trafficking and turnover of podocin. Here, we discover a three amino acids-comprising motif regulating intracellular localization of podocin in cell culture systems. Mutations of this motif led to markedly reduced degradation of podocin. These findings give novel insight into the molecular biology of the slit diaphragm protein podocin, enabling future research to establish the biological relevance of podocin turnover and localization.
Highlights
Podocytes are specialized epithelial cells constituting an essential part of the glomerular filtration barrier
We demonstrated that next to the plasmamembrane a considerable amount of podocin localizes to the late endosomal compartment, where it colocalizes with CD63/LAMP3 partially overlapping with acidic organelles
We proposed a role of the C-terminus in regulating plasma membrane expression of podocin, suggested by markedly increased plasma membrane localization and reduced internalization of a truncation lacking the C-terminus
Summary
Podocytes are specialized epithelial cells constituting an essential part of the glomerular filtration barrier. They form a delicate network of cell extensions, so called primary and secondary processes that enwrap the glomerular capillaries. Interdigitating secondary processes are connected by a specialized cell junction, the slit diaphragm. Composition of the slit diaphragm is essential for various cellular functions of the podocyte such as cell survival, polarity and cytoskeletal organization [1,2]. Expression of its gene product, the PHB-domain containing protein podocin, has only been shown in the glomerular podocyte and testis Sertoli cells [8]. Several disease causing NPHS2 mutations were shown to interfere with podocin intracellular trafficking [11]
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