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The ubiquitin ligase Ubr4 controls disassembly and stability of mechanosensitive podocin/MEC‐2 ion channel supercomplexes
Author(s) -
Rinschen Markus M,
Benzing Thomas
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1221.2
Subject(s) - podocin , ubiquitin , microbiology and biotechnology , ubiquitin ligase , mechanosensitive channels , proteostasis , biology , biochemistry , chemistry , podocyte , ion channel , kidney , genetics , receptor , gene , proteinuria
The kidney expressed PHB‐domain protein podocin maintains the renal filtration barrier. Podocin and its C. elegans orthologue MEC‐2 have emerged as key components of mechanosensitive membrane protein signalling complexes. Whereas podocin resides at a specialized cell junction at the kidney filtration barrier, MEC‐2 is found in neurons required for touch sensitivity. Here we show that the ubiquitin ligase Ubr4 binds to and colocalizes with podocin in kidney podocytes and regulates podocin stability. We also find that this process is conserved in C. elegans and responsible for the degradation of mislocalized MEC‐2 multimers. Surprisingly, degradation depends on Ubr4‐dependent ubiquitylation of very specific lysine residues in the PHB‐domain that are conserved in evolution. Molecular dynamics simulations revealed that ubiquitylation of these sites does not only target podocin/MEC‐2 for proteasomal degradation but may also affect stability and disassembly of the multimeric complex. We suggest that ubiquitylation of specific lysine residues may represent an evolutionarily conserved principle in proteostasis of podocin/MEC‐2 supercomplexes. Support or Funding Information DFG