Research directions
Role of ubiquitylation in the control of Na-homeostasis and blood pressure
In our laboratory we are interested in the physiological and pathophysiological role of ubiquitylation in the control of Na+ balance and blood pressure. This regulation involves the epithelial Na+ channel ENaC in the distal nephron, a channel that is tightly governed by hormones including aldosterone, vasopressin and insulin. Our work has demonstrated that some of the involved regulatory pathways involve modulation of the ubiquitylation level ENaC via the ubiquitin-protein ligase Nedd4-2, thereby reducing ENaC density at the cell surface. In Liddle's syndrome, an inherited disease of salt-sensitive hypertension, the regulation by Nedd4-2 is impaired, causing constitutive Na+-reabsorption via ENaC and consequently hypertension. The activity of Nedd4-2 is regulated by the aldosterone-inducible Sgk1 kinase, which phosphorylates Nedd4-2, thereby recruiting 14-3-3 proteins and interfering with Nedd4-2/ENaC interaction. In recent years it has become apparent that ubiquitylation is a reversible process, involving deubiquitylating enzymes (DUBs). The elucidation of the function of these enzymes, of which more than one hundred are predicted by the human genome, has just begun, and this field is in an extremely rapidly growing phase. We have identified several DUBs whose expression is regulated by aldosterone or vasopressin, and which are able to regulate ENaC by counteracting Nedd4-2 action. We are currently investigating these novel mechanisms, both in vitro and in vivo, using different models including Xenopus laevis oocytes, various epithelial and non-epithelial cell lines and novel transgenic mouse models
