on the tissue. Function NEDD4L is a ubiquitin-protein ligase (E3) that accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then transfers it to specific substrates. In vivo NEDD4-2 regulates ENaC in the lung and kidney, the renal NCC and several Navs. It has also been shown to regulate EGFR, TGFβ receptor and WNT signalling. NEDD4L has been implicated in viral budding and viral latency processes via ubiquitination of viral proteins. In vitro data implicate NEDD4-2 in the regulation of many other proteins, including several ion channels and transporters. However most of these results have not been validated in vivo. Regulation of NEDD4-2 NDFIP1 and NDFIP2 proteins bind NEDD4-2 and regulate its activity and/or interaction with substrates. NEDD4-2 phosphorylation by kinases SGK1 and AKT in response to insulin and aldosterone signaling results in its interaction with 14-3-3 proteins. 14-3-3 binding to NEDD4-2 inhibits its ability to bind and ubiquitinate its substrates (such the ENaC subunits). Autoubiquitination and deubiquitylation of NEDD4-2 by USP2-45 are also known to maintain NEDD4-2 protein stability. Clinical significance NEDD4L is a critical regulator of renal ENaC and NCC and malfunction of this pathway has been linked to hypertension, as in Liddle's syndrome, a genetic disorder where mutations in the ENaC subunits abrogate NEDD4L binding. In mouse, NEDD4-2 deletion leads to increased cell surface expression and activity of ENaC in the lung, resulting in premature clearance of lung fluid, airway drying, lung inflammation and perinatal lethality. Specific deletion of NEDD4-2 in mouse renal tubules leads to increased expression of ENaC and NCC. Consistent with the critical function in ENaC and NCC regulation, NEDDL polymorphisms are linked to essential hypertension in certain human populations. Specific deletion of NEDD4-2 in mouse neurons results in axonal branching defects. Isolated fetal cortical neurons from NEDD4-2 knockout mice show defective regulation of voltage-gated sodium currents, and in animal models of neuropathic pain NEDD4-2 expression has been found to be downregulated. Also NEDD4-2-deficiency results in hyperexcitability of DRG neurons and contributes to pathological pain Interactions NEDD4L has been shown to interact with SCNN1A. Notes References Further reading Human proteins