Glucocorticoid-induced Leucine zipper 1 stimulates the epithelial sodium channel by regulating serum- and glucocorticoid-induced kinase 1 stability and subcellular localization.
Serum- and glucocorticoid-induced kinase 1 (SGK1) is a multifunctional protein kinase that markedly influences various cellular processes such as proliferation, apoptosis, glucose metabolism, and sodium (Na(+)) transport via the epithelial Na(+) channel, ENaC. SGK1 is a short-lived protein, which is predominantly targeted to the endoplasmic reticulum (ER) to undergo rapid proteasome-mediated degradation through the ER-associated degradation (ERAD) system. We show here that the aldosterone-induced chaperone, GILZ1 (glucocorticoid-induced leucine zipper protein-1) selectively decreases SGK1 localization to ER as well as its interaction with ER-associated E3 ubiquitin ligases, HRD1 and CHIP. GILZ1 inhibits SGK1 ubiquitinylation and subsequent proteasome-mediated degradation, thereby prolonging its half-life and increasing its steady-state expression. Furthermore, comparison of the effect of GILZ1 with that of proteasome inhibition (by MG-132) supports the idea that these effects of GILZ1 are secondary to physical interaction of GILZ1 with SGK1 and enhanced recruitment of SGK1 to targets within an "ENaC regulatory complex," thus making less SGK1 available to the ERAD machinery. Finally, effects of GILZ1 knockdown and overexpression strongly support the idea that these effects of GILZ1 are functionally important for ENaC regulation. These data provide new insight into how the manifold activities of SGK1 are selectively deployed and strengthened through modulation of its molecular interactions, subcellular localization, and stability.
Soundararajan
Rama
R
Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, California 94143, USA.
Wang
Jian
J
Melters
Daniël
D
Pearce
David
D
D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D053503:Epithelial Sodium Channels / Q000276:immunology / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000502:physiology*; D000099184:Serum-Glucocorticoid Regulated Kinases
D053503:Epithelial Sodium Channels; D017874:Immediate-Early Proteins; D017346:Protein Serine-Threonine Kinases; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; D000099184:Serum-Glucocorticoid Regulated Kinases; C404226:TSC22D3 protein, human; C467728:STUB1 protein, human; C482345:SYVN1 protein, human