ORCID Profile
0000-0001-9142-6135
Current Organisation
University of South Australia
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Publisher: Springer Science and Business Media LLC
Date: 12-02-2010
DOI: 10.1038/CDD.2010.12
Abstract: The centrosome is the primary microtubule organising centre of the cell. It is composed of many proteins, some of which make up the core of the centrosome, whereas others are used for specific functions. Although the cellular roles of many centrosomal proteins are well defined, much less is known about their functions and the role of the centrosome in development. In this study we investigated the function of NEDD1, a critical component of the centrosome essential for microtubule nucleation, in zebrafish (Danio rerio) development. The zebrafish homologue of NEDD1 (zNEDD1) was cloned and found to have a similar localisation and function to mammalian NEDD1. We show that zNEDD1 is essential for survival, as a high level of knockdown was embryonic lethal. Partial knockdown of zNEDD1 caused abnormalities including an increase in mitotic and apoptotic cells. Pronounced phenotypic defects were seen in the brain, with a lack of defined brain structures, incomplete neural tube formation and a disorganisation of neurons. In addition, we show that a reduction in zNEDD1 resulted in the loss of gamma-tubulin at the centrosome. Our data thus demonstrate that zNEDD1 is critical for the recruitment of gamma-tubulin to the centrosome, and is essential for the proper development of zebrafish.
Publisher: Springer Science and Business Media LLC
Date: 14-04-2021
DOI: 10.1038/S41419-021-03688-7
Abstract: Kidney disease progression can be affected by Na + abundance. A key regulator of Na + homeostasis is the ubiquitin ligase NEDD4-2 and its deficiency leads to increased Na + transport activity and salt-sensitive progressive kidney damage. However, the mechanisms responsible for high Na + induced damage remain poorly understood. Here we show that a high Na + diet compromised kidney function in Nedd4-2 -deficient mice, indicative of progression toward end-stage renal disease. Injury was characterized by enhanced tubule dilation and extracellular matrix accumulation, together with sustained activation of both Wnt/β-catenin and TGF-β signaling. Nedd4-2 knockout in cortical collecting duct cells also activated these pathways and led to epithelial–mesenchymal transition. Furthermore, low dietary Na + rescued kidney disease in Nedd4-2 -deficient mice and silenced Wnt/β-catenin and TGF-β signaling. Our study reveals the important role of NEDD4-2-dependent ubiquitination in Na + homeostasis and protecting against aberrant Wnt/β-catenin/TGF-β signaling in progressive kidney disease.
Publisher: Elsevier BV
Date: 02-2015
Publisher: Informa UK Limited
Date: 07-07-2023
Publisher: Springer Science and Business Media LLC
Date: 09-2017
DOI: 10.1038/CDD.2017.137
Publisher: Informa UK Limited
Date: 28-10-2020
Publisher: Informa UK Limited
Date: 26-12-2017
Publisher: Elsevier BV
Date: 08-2018
DOI: 10.1016/J.TIBS.2018.06.004
Abstract: Protein modification by ubiquitination plays a key evolutionarily conserved role in regulating membrane proteins. Nedd4-2, a ubiquitin ligase, targets membrane proteins such as ion channels and transporters for ubiquitination. This Nedd4-2-mediated ubiquitination provides a crucial step in controlling the membrane availability of these proteins, thus affecting their signaling and physiological outcomes. In one well-studied ex le, Nedd4-2 fine-tunes the physiological function of the epithelial sodium channel (ENaC), thus modulating Na
Publisher: Springer Science and Business Media LLC
Date: 04-12-2020
DOI: 10.1038/S41418-019-0468-5
Abstract: Salt homeostasis is maintained by tight control of Na + filtration and reabsorption. In the distal part of the nephron the ubiquitin protein ligase Nedd4-2 regulates membrane abundance and thus activity of the epithelial Na + channel (ENaC), which is rate-limiting for Na + reabsorption. Nedd4-2 deficiency in mouse results in elevated ENaC and nephropathy, however the contribution of dietary salt to this has not been characterized. In this study we show that high dietary Na + exacerbated kidney injury in Nedd4-2 -deficient mice, significantly perturbing normal postnatal nephrogenesis and resulting in multifocal areas of renal dysplasia, increased markers of kidney injury and a decline in renal function. In control mice, high dietary Na + resulted in reduced levels of ENaC. However, Nedd4-2 -deficient kidneys maintained elevated ENaC even after high dietary Na + , suggesting that the inability to efficiently downregulate ENaC is responsible for the salt-sensitivity of disease. Importantly, low dietary Na + significantly ameliorated nephropathy in Nedd4-2 -deficient mice. Our results demonstrate that due to dysregulation of ENaC, kidney injury in Nedd4-2 -deficient mice is sensitive to dietary Na + , which may have implications in the management of disease in patients with kidney disease.
Publisher: Public Library of Science (PLoS)
Date: 10-03-2010
Publisher: Elsevier BV
Date: 07-2020
Publisher: Springer Science and Business Media LLC
Date: 15-04-2010
Publisher: Portland Press Ltd.
Date: 10-12-2014
DOI: 10.1042/BJ20131275
Abstract: Nedd4-2, a HECT (homologous with E6-associated protein C-terminus)-type ubiquitin protein ligase, has been implicated in regulating several ion channels, including Navs (voltage-gated sodium channels). In Xenopus oocytes Nedd4-2 strongly inhibits the activity of multiple Navs. However, the conditions under which Nedd4-2 mediates native Nav regulation remain uncharacterized. Using Nedd4-2-deficient mice, we demonstrate in the present study that in foetal cortical neurons Nedd4-2 regulates Navs specifically in response to elevated intracellular Na+, but does not affect steady-state Nav activity. In dorsal root ganglia neurons from the same mice, however, Nedd4-2 does not control Nav activities. The results of the present study provide the first physiological evidence for an essential function of Nedd4-2 in regulating Navs in the central nervous system.
Publisher: Wiley
Date: 02-2022
DOI: 10.1002/JEV2.12188
Abstract: Extracellular vesicles (EVs) are important mediators of intercellular communication. However, EV biogenesis remains poorly understood. We previously defined a role for Arrdc4 (Arrestin domain containing protein 4), an adaptor for Nedd4 family ubiquitin ligases, in the biogenesis of EVs. Here we report that ubiquitination of Arrdc4 is critical for its role in EV secretion. We identified five potential ubiquitinated lysine residues in Arrdc4 using mass spectrometry. By analysing Arrdc4 lysine mutants we discovered that lysine 270 (K270) is critical for Arrdc4 function in EV biogenesis. Arrdc4 K270R mutation caused a decrease in the number of EVs released by cells compared to Arrdc4 WT , and a reduction in trafficking of alent metal transporter (DMT1) into EVs. Furthermore, we also observed a decrease in DMT1 activity and an increase in its intracellular degradation in the presence of Arrdc4 K270R . K270 was found to be ubiquitinated with K‐29 polyubiquitin chains by the ubiquitin ligase Nedd4‐2. Thus, our results uncover a novel role of K‐29 polyubiquitin chains in Arrdc4‐mediated EV biogenesis and protein trafficking.
No related grants have been discovered for Jantina Manning.