NEDD4L

Official Full Name

NEDD4 like E3 ubiquitin protein ligase

Organism

Homo sapiens

GeneID

23327

Background

This gene encodes a member of the Nedd4 family of HECT domain E3 ubiquitin ligases. HECT domain E3 ubiquitin ligases transfer ubiquitin from E2 ubiquitin-conjugating enzymes to protein substrates, thus targeting specific proteins for lysosomal degradation. The encoded protein mediates the ubiquitination of multiple target substrates and plays a critical role in epithelial sodium transport by regulating the cell surface expression of the epithelial sodium channel, ENaC. Single nucleotide polymorphisms in this gene may be associated with essential hypertension. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Mar 2012]

Synonyms

RSP5; PVNH7; NEDD4-2; NEDD4.2; hNEDD4-2;

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Detailed Information

Neural precursor cell-expressed developmentally down-regulated gene 4-like (Nedd4L) mRNA is highly expressed in liver, kidney, lung and heart tissues. Numerous studies have found that Nedd4L is closely related to the development and treatment of various diseases in humans.

Nedd4L Gene Locus and Mode of Action

Nedd4L is located on the human chromosome 18q2l.31 and contains 38 exons. All Nedd4L proteins have the same domain (C2 domain + 4 WW domains + HECT domain). Nedd4L can act on epithelial sodium channel (ENaC), Na-Cl co-transporter (NCC), voltage-gated sodium channels (NAV), potassium channel (KCNQ), etc. (1) ENaC is a heterotrimer composed of three subunits (α, β and γ) with two transmembrane domains. Normally functioning ENaC maintains sodium balance in the body, maintains blood pressure, clears alveolar fluid and gases. The exchange is crucial. In vivo experiments showed that the WW domain of Nedd4L can directly bind to the PY motif at the carboxyl end of the three subunits of ENaC to ubiquitinate ENaC and down-regulate the expression of ENaC. (2) It was found that Ned4L was deficient in SD rat renal tubular cells or cultured mDCT cells, and studies have suggested that Nedd4L can interact with Xenopus oocytes and NCCs on the surface of transfected cells. It is ubiquitinated to reduce the expression of NCC and reduce the activity, but it is not clear how these two proteins interact because NCC has no typical PY motif. (3) Seven NAVs in the NAV family contain a PY motif that can be combined with the 3WW or 4WW domain of Nedd4L. In human Embryonic Kidney (HEK), cardiac NAv1.5 can be inhibited by Nedd4L co-expression.

Figure 1. Structural Basis of the Activation and Degradation Mechanisms of the E3 Ubiquitin Ligase Nedd4L. (Escobedo, A., et al. 2014)

Nedd4L and Human Diseases

Studies have confirmed that Nedd4L is closely related to non-small cell lung cancer, gastric cancer, poor prognosis of glioma, colorectal cancer, bladder cancer, and Sezary syndrome. Recent studies have found that Nedd4L gene silencing can slow the growth of melanoma cells in culture. Overexpression of Nedd4L promotes the growth of melanoma cells in allogeneic transplantation models. In pancreatic ductal adenocarcinoma (PDAC), Nedd4L attenuates the proliferation of PDAC cells by miR21, miR23a and miR27a, in Wnt/β-catenin signaling. Nedd4L is expressed at a high level in human hepatocellular carcinoma. The rs4149601(G/A) gene frameshift mutation results in a truncated protein encoding and is an occult cleavage site for the Nedd4L gene. Functional studies have shown that this gene mutation can cause an increase in sodium ion reabsorption through the epithelial sodium channel (ENaC-Nedd4L-SGK1), which plays an important role in regulating blood pressure in the body.

In human embryonic kidney cell HEK293T, Nedd4L can degrade phosphorylation of Smad3 by ubiquitination, which limits the signaling pathway of TGF-β1. Inhibition of Nedd4L activity or reduced expression by proteasome inhibitor MG132 or RNAi technology increased TGF-β1-induced phosphorylation of Smad2/3 and PAI-1 expression. It is reported in the literature that unlike other kinases, Nedd4L is active in resting cells and maintains the ubiquitination state of the target protein. When it is phosphorylated, it loses its enzymatic activity.

References:

Wang, T. , Hogan-Cann, A. , Kang, Y. , Cui, Z. , & Zhang, S. . (2014). Muscarinic receptor activation increases herg channel expression through phosphorylation of ubiquitin ligase nedd4-2. Molecular pharmacology, 85(6), 877.
Trimpert, C., Wesche, D., Groot, T. D., Rodriguez, M. M. P., Wong, V., & Berg, D. T. M. V. D., et al. (2017). Ndfip allows nedd4/nedd4l-induced aqp2 ubiquitination and degradation. Plos One, 12(9), e0183774.
Escobedo, A. , Gomes, T. , Aragón, Eric, Martín-Malpartida, Pau, Ruiz, L. , & Macias, M. . (2014). Structural basis of the activation and degradation mechanisms of the e3 ubiquitin ligase nedd4l. Structure, 22(10), 1446-1457.

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