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Abstract: FR-PO687

The E3 Ubiquitin Ligase HUWE1 Is a Central Regulator of Podocyte Homeostasis

Session Information

Category: Glomerular Diseases

  • 1304 Glomerular Diseases: Podocyte Biology


  • Volker, Linus A., University Hospital of Cologne, Cologne, NRW, Germany
  • Brinkkoetter, Paul T., University Hospital of Cologne, Cologne, NRW, Germany
  • Schermer, Bernhard, University Hospital of Cologne, Cologne, NRW, Germany
  • Benzing, Thomas, University Hospital of Cologne, Cologne, NRW, Germany
  • Höhne, Martin, University Hospital of Cologne, Cologne, NRW, Germany

Terminal differentiation is a hallmark of renal podocytes. As terminally differentiated cells, podocytes need tight control of homeostasis. This is achieved through various signaling cascades such as mTOR, MAP-kinase signaling, AKT, and Wnt/Notch acting on diverse processes like proteostasis, DNA-damage repair, energy homeostasis and others. We identified the ultra-large E3 HECT-type ubiquitin-ligase HUWE1 as an interactor of the slit diaphragm associated protein complex. HUWE1 features a circular protein-protein interaction domain rendering it highly context-sensitive and versatile as a central modifier of intracellular signaling events via ubiquitination.


A podocyte-specific knockout mouse model of HUWE1 and shRNA- and CRISPR/Cas9-engineered podocyte cell-lines were used to elucidate the effects of HUWE1 on kidney function, podocyte homeostasis, and intracellular signaling. We employed a three-tiered multiomics approach including transcriptomics, proteomics, and ubiquitinomics to unravel the profound changes in podocyte homeostasis induced by HUWE1-deficiency.


HUWE1-deficient mice develope albuminuria and progressive kidney failure at week 4. They develope severe glomerular damage and foot process effacement on the ultrastructural level. Huwe1-deficient mice die at week 7 to 14. Huwe1-deficient podocytes showe decreased migratory activity and a general reduction in protein turn-over in the 26S proteasome fluorogenic peptidase assay, indicating defects in proteostasis. All three tiers of the multiomics approach demonstrated profound alterations in response to HUWE1-deficiency. An integrated analysis revealed podocyte-specific defects in mitochondrial energy metabolism, cell cycle and differentiation control, and actin cytoskeleton rearrangement. Moreover, a HUWE1-protein interaction network overlapped significantly with targets of mir193b-3p, a microRNA closely related to mir193a-3p, a known inductor of podocytopathy and FSGS.


HUWE1-deficiency causes a disruption of podocyte homeostasis via interaction with microRNA-associated networks and global changes in proteostasis, energy metabolism, cell cycle control, and actin cytoskeleton regulation.


  • Private Foundation Support