Ubiquitylation of Ion Channels

Hugues Abriel; Olivier Staub

doi:10.1152/physiol.00033.2005

Ubiquitylation of Ion Channels

Physiology ◽

10.1152/physiol.00033.2005 ◽

2005 ◽

Vol 20 (6) ◽

pp. 398-407 ◽

Cited By ~ 59

Author(s):

Hugues Abriel ◽

Olivier Staub

Keyword(s):

Endoplasmic Reticulum ◽

Ion Channels ◽

Covalent Attachment ◽

Endoplasmic Reticulum Associated Degradation ◽

Protein Ligases

Ubiquitylation (i.e., covalent attachment of ubiquitin moieties to proteins) of ion channels allows regulation of their activity and fate. Nedd4/Nedd4-like ubiquitin-protein ligases bind to, ubiquitylate, and modulate the internalization of several channels bearing PY motifs, whereas endoplasmic reticulum-associated degradation (involving ubiquitylation) plays an important role in the biogenesis of normal and defective channels.

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SLC26A9 is selected for endoplasmic reticulum associated degradation (ERAD) via Hsp70-dependent targeting of the soluble STAS domain

Biochemical Journal ◽

10.1042/bcj20210644 ◽

2021 ◽

Author(s):

Patrick G Needham ◽

Jennifer L Goeckeler-Fried ◽

Casey Zhang ◽

Zhihao Sun ◽

Adam R Wetzel ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Protein Folding ◽

Ion Channels ◽

Membrane Protein ◽

Secretory Pathway ◽

Expression System ◽

Chloride Ions ◽

Substrate Selection ◽

Endoplasmic Reticulum Associated Degradation ◽

Stas Domain

SLC26A9, a member of the solute carrier protein family, transports chloride ions across various epithelia. SLC26A9 also associates with other ion channels and transporters linked to human health, and in some cases these heterotypic interactions are essential to support the biogenesis of both proteins. Therefore, understanding how this complex membrane protein is initially folded might provide new therapeutic strategies to overcome deficits in the function of SLC26A9 partners, one of which is associated with Cystic Fibrosis. To this end, we developed a novel yeast expression system for SLC26A9. This facile system has been used extensively with other ion channels and transporters to screen for factors that oversee protein folding checkpoints. As commonly observed for other channels and transporters, we first noted that a substantial fraction of SLC26A9 is targeted for endoplasmic reticulum associated degradation (ERAD), which destroys folding-compromised proteins in the early secretory pathway. We next discovered that ERAD selection requires the Hsp70 chaperone, which can play a vital role in ERAD substrate selection. We then created SLC26A9 mutants and found that the transmembrane-rich domain of SLC26A9 was quite stable, whereas the soluble cytosolic STAS domain was responsible for Hsp70-dependent ERAD. To support data obtained in the yeast model, we were able to recapitulate Hsp70-facilitated ERAD of the STAS domain in human tissue culture cells. These results indicate that a critical barrier to nascent membrane protein folding can reside within a specific soluble domain, one that is monitored by components associated with the ERAD machinery.

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