Role of Derlin-1 protein in proteostasis regulation of ATP-sensitive potassium channels.
ATP-sensitive potassium (K(ATP)) channels composed of sulfonylurea receptor 1 (SUR1) and Kir6.2 regulate insulin secretion by linking glucose metabolism with membrane potential. The number of K(ATP) channels in the plasma membrane affects the sensitivity of β-cells to glucose. Aberrant surface channel expression leads to insulin secretion disease. Previously, we have shown that K(ATP) channel proteins undergo endoplasmic reticulum (ER)-associated degradation (ERAD) via the ubiquitin-proteasome pathway, and inhibition of proteasome function results in an increase in channel surface expression. Here, we investigated whether Derlin-1, a protein involved in retrotranslocation of misfolded or misassembled proteins across the ER membrane for degradation by cytosolic proteasomes, plays a role in ERAD and, in turn, biogenesis efficiency of K(ATP) channels. We show that both SUR1 and Kir6.2 form a complex with Derlin-1 and an associated AAA-ATPase, p97. Overexpression of Derlin-1 led to a decrease in the biogenesis efficiency and surface expression of K(ATP) channels. Conversely, knockdown of Derlin-1 by RNA interference resulted in increased processing of SUR1 and a corresponding increase in surface expression of K(ATP) channels. Importantly, knockdown of Derlin-1 increased the abundance of disease-causing misfolded SUR1 or Kir6.2 proteins and even partially rescued surface expression in a mutant channel. We conclude that Derlin-1, by being involved in ERAD of SUR1 and Kir6.2, has a role in modulating the biogenesis efficiency and surface expression of K(ATP) channels. The results suggest that physiological or pathological changes in Derlin-1 expression levels may affect glucose-stimulated insulin secretion by altering surface expression of K(ATP) channels.
Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon 97239.
Fang
F
Wang
Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon 97239.
Erik M
EM
Olson
Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon 97239. Electronic address: shyngs@ohsu.edu.
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SL
Shyng
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D006224:Cricetinae; D060746:Endoplasmic Reticulum-Associated Degradation / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D011955:Receptors, Drug / Q000235:genetics / Q000378:metabolism*; D064233:Sulfonylurea Receptors; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D000099161:Kcnj11 Channel
D018528:ATP-Binding Cassette Transporters; D000251:Adenosine Triphosphatases; D007328:Insulin; D008565:Membrane Proteins; D009687:Nuclear Proteins; D024661:Potassium Channels, Inwardly Rectifying; D046988:Proteasome Endopeptidase Complex; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D025801:Ubiquitin; D000099161:Kcnj11 Channel; C577507:ABCC8 protein, human; C487709:DERL1 protein, human; C404942:p97 ATPase