Endoplasmic reticulum–associated degradation of the renal potassium channel, ROMK, leads to type II Bartter syndrome

@article{ODonnell2017EndoplasmicRD,
  title={Endoplasmic reticulum–associated degradation of the renal potassium channel, ROMK, leads to type II Bartter syndrome},
  author={Brighid M. O'Donnell and Timothy D. Mackie and Arohan R. Subramanya and Jeffrey L. Brodsky},
  journal={The Journal of Biological Chemistry},
  year={2017},
  volume={292},
  pages={12813 - 12827}
}
Type II Bartter syndrome is caused by mutations in the renal outer medullary potassium (ROMK) channel, but the molecular mechanisms underlying this disease are poorly defined. To rapidly screen for ROMK function, we developed a yeast expression system and discovered that yeast cells lacking endogenous potassium channels could be rescued by WT ROMK but not by ROMK proteins containing any one of four Bartter mutations. We also found that the mutant proteins were significantly less stable than WT… 

Figures from this paper

The endosomal trafficking factors CORVET and ESCRT suppress plasma membrane residence of the renal outer medullary potassium channel (ROMK)
TLDR
The results indicate that components of the post-endocytic pathway influence the cell-surface density of ROMK and establish that components in this pathway modulate channel activity.
Disease Associated Mutations in KIR Proteins Linked to Aberrant Inward Rectifier Channel Trafficking
TLDR
Structural mapping of the trafficking defect causing mutations provided a 3D framework, which indicates that trafficking deficient mutations form clusters, which affect trafficking by different mechanisms, including protein stability.
New insights into the role of endoplasmic reticulum‐associated degradation in Bartter Syndrome Type 1
TLDR
The study reveals that BS1 is among diseases linked to the ERAD pathway, and opens the possibility that maturation of some ER retained NKCC2 variants is correctable by chemical chaperones offering, therefore, promising avenues in elucidating the molecular pathways governing the ERad of NK CC2 folding mutants.
Golgi Alpha1,2-Mannosidase IA Promotes Efficient Endoplasmic Reticulum-Associated Degradation of NKCC2
TLDR
The identification of Golgi alpha1, 2-mannosidase IA (ManIA) as a novel binding partner of the immature form of NKCC2 is reported, suggesting a model whereby Golgi ManIA contributes to ERAD ofNKCC2, by promoting the retention, recycling, and ERad of misfolded proteins that initially escape protein quality control surveillance within the ER.
Abnormally decreased renal Klotho is linked to endoplasmic reticulum-associated degradation in mice
TLDR
UUO induced severe kidney injuries and RIF and its specific inhibition significantly promoted Klotho expression, possibly through enhanced UPR, suggest that UPR was remarkably enhanced in the presence of ERAD inhibition and compensated for excess improperly folded proteins, subsequently contributing to the additional production of mature Klotha protein.
Select α-arrestins control cell-surface abundance of the mammalian Kir2.1 potassium channel in a yeast model
TLDR
These findings implicate α-arrestins in regulating an additional class of plasma membrane proteins and establish a new tool for dissecting the trafficking itinerary of any membrane protein in yeast.
Investigating Potassium Channels in Budding Yeast: A Genetic Sandbox
TLDR
An overview of the major genetic tools used to study potassium channels in S. cerevisiae is provided, a survey of seminal studies utilizing these tools, and a prospective for the future use of this elegant genetic approach is proposed.
Complementary computational and experimental evaluation of missense variants in the ROMK potassium channel
The renal outer medullary potassium (ROMK) channel is essential for potassium transport in the kidney, and its dysfunction is associated with a salt-wasting disorder known as Bartter syndrome.
...
...

References

SHOWING 1-10 OF 129 REFERENCES
Functional implications of mutations in the human renal outer medullary potassium channel (ROMK2) identified in Bartter syndrome
TLDR
This study has unraveled three distinct mechanisms by which mutations in hROMK2 could impair channel function in Bartter syndrome and specific pharmacological treatments could be considered for each group of mutations.
Small heat-shock proteins select deltaF508-CFTR for endoplasmic reticulum-associated degradation.
TLDR
It is suggested that sHsps maintain the solubility of DeltaF508-CFTR during the ERAD of this polypeptide, which is not essential for polyubiquitination.
Hsp70 molecular chaperone facilitates endoplasmic reticulum-associated protein degradation of cystic fibrosis transmembrane conductance regulator in yeast.
TLDR
The fate of the cystic fibrosis transmembrane conductance regulator (CFTR) in the yeast Saccharomyces cerevisiae is studied, indicating that CFTR resides in the ER and is stabilized in strains defective for proteasome activity or deleted for the ubiquitin-conjugating enzymes Ubc6p and Ubc7p, thus demonstrating thatCFTR is a bona fide ERAD substrate in yeast.
A Phosphorylation-dependent Export Structure in ROMK (Kir 1.1) Channel Overrides an Endoplasmic Reticulum Localization Signal*
TLDR
Studies in Xenopus oocytes and ROMK channels indicate that phosphorylation of Ser44 drives an export step within the secretory pathway to override an independent endoplasmic reticulum localization signal.
ENaC Degradation in A6 Cells by the Ubiquitin-Proteosome Proteolytic Pathway*
TLDR
It is found that the inhibitor, MG-132, increases amiloride-sensitive trans-epithelial current in Xenopus distal nephron A6 cells and suggests that in native renal cells the proteosomal pathway is an important regulator of ENaC function.
Regulation of stability and function of the epithelial Na+ channel (ENaC) by ubiquitination
TLDR
It is shown that ENaC is a short‐lived protein that is ubiquitinated in vivo on the α and γ (but not β) subunits, and a paradigm for ubiquitination‐mediated regulation of ion channels is proposed.
Proteasome-dependent endoplasmic reticulum-associated protein degradation: an unconventional route to a familiar fate.
Proteasome-dependent endoplasmic reticulum-associated protein degradation: An unconventional route to a familiar fate
TLDR
It is concluded that lumenal ERAD substrates are exported from the yeast ER to the cytoplasm for degradation by the proteasome complex.
...
...