Results

RDF/XMLNTriplesTurtleShow queryShare
SubjectPredicateObject
http://purl.uniprot.org/citations/33443052http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/33443052http://www.w3.org/2000/01/rdf-schema#comment"

Background

FSGS caused by mutations in INF2 is characterized by a podocytopathy with mistrafficked nephrin, an essential component of the slit diaphragm. Because INF2 is a formin-type actin nucleator, research has focused on its actin-regulating function, providing an important but incomplete insight into how these mutations lead to podocytopathy. A yeast two-hybridization screen identified the interaction between INF2 and the dynein transport complex, suggesting a newly recognized role of INF2 in regulating dynein-mediated vesicular trafficking in podocytes.

Methods

Live cell and quantitative imaging, fluorescent and surface biotinylation-based trafficking assays in cultured podocytes, and a new puromycin aminoglycoside nephropathy model of INF2 transgenic mice were used to demonstrate altered dynein-mediated trafficking of nephrin in INF2 associated podocytopathy.

Results

Pathogenic INF2 mutations disrupt an interaction of INF2 with dynein light chain 1, a key dynein component. The best-studied mutation, R218Q, diverts dynein-mediated postendocytic sorting of nephrin from recycling endosomes to lysosomes for degradation. Antagonizing dynein-mediated transport can rescue this effect. Augmented dynein-mediated trafficking and degradation of nephrin underlies puromycin aminoglycoside-induced podocytopathy and FSGS in vivo.

Conclusions

INF2 mutations enhance dynein-mediated trafficking of nephrin to proteolytic pathways, diminishing its recycling required for maintaining slit diaphragm integrity. The recognition that dysregulated dynein-mediated transport of nephrin in R218Q knockin podocytes opens an avenue for developing targeted therapy for INF2-mediated FSGS."xsd:string
http://purl.uniprot.org/citations/33443052http://purl.org/dc/terms/identifier"doi:10.1681/asn.2020081109"xsd:string
http://purl.uniprot.org/citations/33443052http://purl.uniprot.org/core/author"Sun H."xsd:string
http://purl.uniprot.org/citations/33443052http://purl.uniprot.org/core/author"Pollak M.R."xsd:string
http://purl.uniprot.org/citations/33443052http://purl.uniprot.org/core/author"Schlondorff J.S."xsd:string
http://purl.uniprot.org/citations/33443052http://purl.uniprot.org/core/author"Subramanian B."xsd:string
http://purl.uniprot.org/citations/33443052http://purl.uniprot.org/core/author"Perez-Gill C."xsd:string
http://purl.uniprot.org/citations/33443052http://purl.uniprot.org/core/date"2021"xsd:gYear
http://purl.uniprot.org/citations/33443052http://purl.uniprot.org/core/name"J Am Soc Nephrol"xsd:string
http://purl.uniprot.org/citations/33443052http://purl.uniprot.org/core/pages"307-322"xsd:string
http://purl.uniprot.org/citations/33443052http://purl.uniprot.org/core/title"Dysregulated Dynein-Mediated Trafficking of Nephrin Causes INF2-related Podocytopathy."xsd:string
http://purl.uniprot.org/citations/33443052http://purl.uniprot.org/core/volume"32"xsd:string
http://purl.uniprot.org/citations/33443052http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/33443052
http://purl.uniprot.org/citations/33443052http://xmlns.com/foaf/0.1/primaryTopicOfhttps://pubmed.ncbi.nlm.nih.gov/33443052
http://purl.uniprot.org/uniprot/#_E9QLA5-mappedCitation-33443052http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/33443052
http://purl.uniprot.org/uniprot/#_Q0GNC1-mappedCitation-33443052http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/33443052
http://purl.uniprot.org/uniprot/Q0GNC1http://purl.uniprot.org/core/mappedCitationhttp://purl.uniprot.org/citations/33443052
http://purl.uniprot.org/uniprot/E9QLA5http://purl.uniprot.org/core/mappedCitationhttp://purl.uniprot.org/citations/33443052