2LAJ, 2LB2, 2LTY, 2MPT, 2NSQ, 2ONI, 3JVZ, 3JW0, 5HPK2332783814ENSG00000049759ENSMUSG00000024589Q96PU5Q8CFI0NM_001144969NM_001144970NM_001144971NM_001243960NM_015277NM_001114386NM_031881NP_001138441NP_001138442NP_001138443NP_001230889NP_056092NP_001390942Neural precursor cell expressed developmentally downregulated gene 4-like (NEDD4L) or NEDD4-2 is an enzyme (ubiquitin ligase) of the NEDD4 family.

NEDD4-2 has been shown to ubiquitinate and therefore down regulate the epithelial sodium channel (ENaC) in the collecting ducts of the kidneys, therefore opposing the actions of aldosterone and increasing salt excretion.

In Liddle's Syndrome NEDD4 is unable to bind to the ENaC and lead to salt retention and hypertension occur.

[15][17] 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.

[24][25] NEDD4-2 phosphorylation by kinases SGK1 and AKT in response to insulin and aldosterone signaling results in its interaction with 14-3-3 proteins.

Consistent with the critical function in ENaC and NCC regulation, NEDDL polymorphisms are linked to essential hypertension in certain human populations.

[37] Isolated fetal cortical neurons from NEDD4-2 knockout mice show defective regulation of voltage-gated sodium currents,[38] and in animal models of neuropathic pain NEDD4-2 expression has been found to be downregulated.