Journal article
Dysregulated Dynein-Mediated Trafficking of Nephrin Causes INF2-related Podocytopathy
Journal of the American Society of Nephrology, Vol.32(2), pp.307-322
02/01/2021
DOI: 10.1681/ASN.2020081109
PMCID: PMC8054882
PMID: 33443052
Abstract
FSGS caused by mutations in
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.
Live cell and quantitative imaging, fluorescent and surface biotinylation-based trafficking assays in cultured podocytes, and a new puromycin aminoglycoside nephropathy model of
transgenic mice were used to demonstrate altered dynein-mediated trafficking of nephrin in INF2 associated podocytopathy.
Pathogenic
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
.
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.
Details
- Title: Subtitle
- Dysregulated Dynein-Mediated Trafficking of Nephrin Causes INF2-related Podocytopathy
- Creators
- Hua Sun - Beth Israel Deaconess Medical CenterChandra Perez-Gill - Beth Israel Deaconess Medical CenterJohannes S Schlöndorff - Beth Israel Deaconess Medical CenterBalajikarthick Subramanian - Beth Israel Deaconess Medical CenterMartin R Pollak - Beth Israel Deaconess Medical Center
- Resource Type
- Journal article
- Publication Details
- Journal of the American Society of Nephrology, Vol.32(2), pp.307-322
- DOI
- 10.1681/ASN.2020081109
- PMID
- 33443052
- PMCID
- PMC8054882
- NLM abbreviation
- J Am Soc Nephrol
- ISSN
- 1046-6673
- eISSN
- 1533-3450
- Grant note
- R01 DK088826 / NIDDK NIH HHS T32 DK007726 / NIDDK NIH HHS
- Language
- English
- Date published
- 02/01/2021
- Academic Unit
- Nephrology, Dialysis and Transplantation; Stead Family Department of Pediatrics
- Record Identifier
- 9984383269902771
Metrics
11 Record Views