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Abstract: PO1970

Dysregulated Dynein-Mediated Vesicle Trafficking Is a New Mechanism of FSGS

Session Information

  • Podocyte Biology
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

  • 1204 Podocyte Biology


  • Sun, Hua, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
  • Pollak, Martin R., Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States

Focal segmental glomerulosclerosis (FSGS) is a deteriorating kidney disease with poor prognosis. The lack of understanding of its mechanism has hindered the development of treatment. Mutations in INF2 cause FSGS characterized by a podocytopathy with mistrafficked slit diaphragm (SD) protein critical for the integrity of the glomerular filtration barrier (GFB). This feature has been found in FSGS of other etiologies, making INF2 related podocytopathy a good model to dissect the disturbed vesicle trafficking in podocytopathies prone to FSGS.

By yeast two hybridization screening we identified the interaction of INF2 with Dynll1, a dynein component. We hypothesize that INF2 regulates dynein mediated vesicle trafficking, which shuttles endocytosed protein to proteolytic system. This interaction could be disrupted by pathogenic mutations in INF2, suggesting dysregulation of dynein mediated trafficking is an underlying mechanism of the disease.


The INF2-Dynll1 interaction was confirmed by yeast mating and CO-IP. The dysregulated dynein mediated trafficking of nephrin was investigated in cultured podocytes by fluorescent based and surface biotinylation based assays, and time-lapse imaging in vitro; and was also demonstrated in the puromycin aminoglycoside induced nephropathy (PAN) of INF2 transgenic mice with knockin (KI) of R218Q, a pathogenic mutant that disrupts INF2/Dynll1 interaction.


1. We demonstrated that INF2 limited dynein mediated retrograde trafficking of nephrin by binding to and sequestering Dynll1, a component essential for the integrity of dynein.

2. R218Q KI podocytes illustrated an impaired recycling of nephrin with enhanced recruitment of dynein components, which could be rescued by targeting dynein transport pathway using Ciliobrevin D (Dynein inhibitor), dominant negative Dynactin 1, siRNA for Dynll1 or overexpression of wildtype INF2 (to sequester Dynll1).

3. PAN of R218Q KI mice was characterized by increased recruitment of Dynll1 to nephrin, correlated to increased ubiquitination and decreased surface nephrin, suggesting an enhanced dynein trafficking pathway underlies the impaired functional trafficking of nephrin, disintegrity of SDs and malfunction of the GFB.


Recognition of the dysregulated dynein mediated trafficking of SD protein has enlightened a new understanding and therapeutic targets for INF2 related podocytopathy and FSGS.


  • NIDDK Support