Nedd4 and Nedd4–2: Closely related ubiquitin-protein ligases with distinct physiological functions

Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Cell death and differentiation (Impact Factor: 8.39). 07/2009; 17(1):68-77. DOI: 10.1038/cdd.2009.84
Source: PubMed

ABSTRACT The Nedd4 (neural precursor cell-expressed developmentally downregulated gene 4) family of ubiquitin ligases (E3s) is characterized by a distinct modular domain architecture, with each member consisting of a C2 domain, 2-4 WW domains, and a HECT-type ligase domain. Of the nine mammalian members of this family, Nedd4 and its close relative, Nedd4-2, represent the ancestral ligases with strong similarity to the yeast, Rsp5. In Saccharomyces cerevisiae Rsp5 has a key role in regulating the trafficking, sorting, and degradation of a large number of proteins in multiple cellular compartments. However, in mammals the Nedd4 family members, including Nedd4 and Nedd4-2, appear to have distinct functions, thereby suggesting that these E3s target specific proteins for ubiquitylation. In this article we focus on the biology and emerging functions of Nedd4 and Nedd4-2, and review recent in vivo studies on these E3s.

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    • "Nedd4-2 regulates other voltage-gated ion channels, such as potassium (K v s and KCNQs) and choride (ClCs) channels, which modulate electrical excitability in neurons (Bongiorno et al. 2011). Nedd4-2 regulation is not restricted to voltage-gated ion channels, but includes interactions with amino acids, dopamine transporters, glutamate transporters, adaptor proteins, and kinases (Yang and Kumar 2009). "
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    ABSTRACT: Ion channel proteins are regulated by different types of posttranslational modifications. The focus of this review is the regulation of voltage-gated sodium channels (Navs) upon their ubiquitylation. The amiloride-sensitive epithelial sodium channel (ENaC) was the first ion channel shown to be regulated upon ubiquitylation. This modification results from the binding of ubiquitin ligase from the Nedd4 family to a protein-protein interaction domain, known as the PY motif, in the ENaC subunits. Many of the Navs have similar PY motifs, which have been demonstrated to be targets of Nedd4-dependent ubiquitylation, tagging them for internalization from the cell surface. The role of Nedd4-dependent regulation of the Nav membrane density in physiology and disease remains poorly understood. Two recent studies have provided evidence that Nedd4-2 is downregulated in dorsal root ganglion (DRG) neurons in both rat and mouse models of nerve injury-induced neuropathic pain. Using two different mouse models, one with a specific knockout of Nedd4-2 in sensory neurons and another where Nedd4-2 was overexpressed with the use of viral vectors, it was demonstrated that the neuropathy-linked neuronal hyperexcitability was the result of Nav1.7 and Nav1.8 overexpression due to Nedd4-2 downregulation. These studies provided the first in vivo evidence of the role of Nedd4-2-dependent regulation of Nav channels in a disease state. This ubiquitylation pathway may be involved in the development of symptoms and diseases linked to Nav-dependent hyperexcitability, such as pain, cardiac arrhythmias, epilepsy, migraine, and myotonias.
    Handbook of experimental pharmacology 01/2014; 221:231-250. DOI:10.1007/978-3-642-41588-3_11
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    • "The ubiquitylation pathway requires the action of three enzymes: E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme) and E3 (ubiquitin ligase) [2]. Nedd4 (neuronal precursor cell-expressed developmentally downregulated 4) is an important family of E3 ubiquitin ligase within the Hect E3s superfamily [3] [4], which have been isolated from yeast to mammal [5] [6]. To better explore the mechanism of Nedd4 E3 ligase, various specific substrates of Nedd4 have been described and characterized in mammals [7] [8], which include Nedd4 binding protein 1(N4BP1) [9]. "
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    ABSTRACT: Nedd4 binding protein 1 (N4BP1) has been identified as an interacting protein and a substrate of Nedd4 E3 ligase. However, the report about N4BP1's function is limit. In this study, a novel N4BP1 gene (CiN4BP1) was cloned from grass carp (Ctenopharyngodon idella). The full-length cDNA sequence of CiN4BP1 (3022 bp) included an open reading frame (ORF) of 2565 bp, which encoded a putative peptides of 854 amino acids containing one KH domain and one NYN domain. It was close homology (47% identify) to Oryzias latipes N4BP1. And mRNA expression of CiN4BP1 gene showed relatively high level in skin, gill, head kidney and spleen. After grass carp reovirus (GCRV) infection, CiN4BP1 was up-regulated in vivo and in vitro. Furthermore, overexpression of CiN4BP1 in CIK cells inhibited viral gene transcription. These data indicated that CiN4BP1 might play an important role in immune response to viral invasion.
    Fish &amp Shellfish Immunology 11/2013; 36(1). DOI:10.1016/j.fsi.2013.11.003 · 3.03 Impact Factor
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    • "The first physiological role for Nedd4 and Nedd4-2-mediated ubiquitination was reported in the epithelial cells of the kidney tubules. It was shown that Nedd4 and Nedd4-2 could regulate membrane levels of ENaC (Yang and Kumar, 2010) through the binding of WW domains to the PY motifs in the cytoplasmic tails of the ENaC subunits. Of interest, the number of WW domains is enriched in humans, rats and mice compared to Drosophila and recently it was demonstrated that only WW3 and WW4 of Nedd4-2 are involved in the regulation of ENaC and substrate recruitment (Fotia et al., 2003). "
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    ABSTRACT: Ubiquitination of proteins by the Nedd4 family of ubiquitin ligases is a significant mechanism in protein trafficking and degradation and provides for tight spatiotemporal regulation. Ubiquitination is gaining increasing recognition as a central mechanism underpinning the regulation of neuronal development and homeostasis in the brain. This review will focus on the Nedd4 and Nedd4-2 E3 ubiquitin ligases that are implicated in an increasing number of neuronal protein-protein interactions. Understanding of the contribution of Nedd4 and Nedd4-2 in regulating key functions in the brain is shedding new light on the ubiquitination signal not only in orchestrating degradation events but also in protein trafficking. Furthermore, the description of several novel Nedd4/4-2 targets in neurons is changing the way we conceptualize how neurons maintain normal function and how this is altered in disease.
    The international journal of biochemistry & cell biology 12/2012; 45(3). DOI:10.1016/j.biocel.2012.12.006 · 4.24 Impact Factor
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