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Nedd4-2

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https://www.readbyqxmd.com/read/28212375/epilepsy-associated-gene-nedd4-2-mediates-neuronal-activity-and-seizure-susceptibility-through-ampa-receptors
#1
Jiuhe Zhu, Kwan Young Lee, Kathryn A Jewett, Heng-Ye Man, Hee Jung Chung, Nien-Pei Tsai
The neural precursor cell expressed developmentally down-regulated gene 4-2, Nedd4-2, is an epilepsy-associated gene with at least three missense mutations identified in epileptic patients. Nedd4-2 encodes a ubiquitin E3 ligase that has high affinity toward binding and ubiquitinating membrane proteins. It is currently unknown how Nedd4-2 mediates neuronal circuit activity and how its dysfunction leads to seizures or epilepsies. In this study, we provide evidence to show that Nedd4-2 mediates neuronal activity and seizure susceptibility through ubiquitination of GluA1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, (AMPAR)...
February 17, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28192531/multi-layered-control-of-galectin-8-mediated-autophagy-during-adenovirus-cell-entry-through-a-conserved-ppxy-motif-in-the-viral-capsid
#2
Charlotte Montespan, Shauna A Marvin, Sisley Austin, Andrew M Burrage, Benoit Roger, Fabienne Rayne, Muriel Faure, Edward M Campell, Carola Schneider, Rudolph Reimer, Kay Grünewald, Christopher M Wiethoff, Harald Wodrich
Cells employ active measures to restrict infection by pathogens, even prior to responses from the innate and humoral immune defenses. In this context selective autophagy is activated upon pathogen induced membrane rupture to sequester and deliver membrane fragments and their pathogen contents for lysosomal degradation. Adenoviruses, which breach the endosome upon entry, escape this fate by penetrating into the cytosol prior to autophagosome sequestration of the ruptured endosome. We show that virus induced membrane damage is recognized through Galectin-8 and sequesters the autophagy receptors NDP52 and p62...
February 13, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28186199/ubiquitination-mediates-kv1-3-endocytosis-as-a-mechanism-for-protein-kinase-c-dependent-modulation
#3
Ramón Martínez-Mármol, Katarzyna Styrczewska, Mireia Pérez-Verdaguer, Albert Vallejo-Gracia, Núria Comes, Alexander Sorkin, Antonio Felipe
The voltage-dependent potassium channel Kv1.3 plays essential physiological functions in the immune system. Kv1.3, regulating the membrane potential, facilitates downstream Ca(2+) -dependent pathways and becomes concentrated in specific membrane microdomains that serve as signaling platforms. Increased and/or delocalized expression of the channel is observed at the onset of several autoimmune diseases. In this work, we show that adenosine (ADO), which is a potent endogenous modulator, stimulates PKC, thereby causing immunosuppression...
February 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28182002/rapamycin-upregulates-glutamate-transporter-and-il-6-expression-in-astrocytes-in-a-mouse-model-of-parkinson-s-disease
#4
Yunlong Zhang, Xiaoliang He, Xiaojuan Wu, Ming Lei, Zhiyun Wei, Xiuping Zhang, Lei Wen, Pingyi Xu, Shaomin Li, Shaogang Qu
Rapamycin protects mice against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced loss of dopaminergic neurons, which is an established model for Parkinson's disease. We demonstrated that rapamycin preserves astrocytic expression of glutamate transporters and glutamate reuptake. The protective effect was also observed in astrocyte cultures, indicating that rapamycin acts directly on astrocytes. In the MPTP model, rapamycin caused reduced expression of the E3 ubiquitin ligase Nedd4-2 (neuronal precursor cell expressed developmentally downregulated 4-2) and reduced colocalization of glutamate transporters with ubiquitin...
February 9, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28151476/regulation-of-glutamate-transporter-trafficking-by-nedd4-2-in-a-parkinson-s-disease-model
#5
Yunlong Zhang, Xiaoliang He, Xingjun Meng, Xiaojuan Wu, Huichun Tong, Xiuping Zhang, Shaogang Qu
Glutamate transporters play a key role in glutamate clearance and protect the central nervous system from glutamate excitotoxicity. Dysfunctional glutamate transporters contribute to the pathogenesis of Parkinson's disease (PD); however, the mechanisms that underlie the regulation of glutamate transporters in PD are still not well characterized. Here we report that Nedd4-2 mediates the ubiquitination of glutamate transporters in 1-methyl-4- phenylpyridinium (MPP(+))-treated astrocytes and in the midbrain of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP)-constructed PD model mice...
February 2, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28087701/the-ubiquitin-ligase-nedd4l-regulates-the-na-k-2cl-co-transporter-nkcc1-slc12a2-in-the-colon
#6
Chong Jiang, Hiroshi Kawabe, Daniela Rotin
The ubiquitin ligase Nedd4-like (Nedd4L, or Nedd4-2) binds to and regulates stability of the epithelial Na+ channel (ENaC) in salt absorbing epithelia in the kidney, lung, and other tissues. Its role in the distal colon, which also absorbs salt and fluid and expresses ENaC, is unknown. Using conditional knockout approach to knockout Nedd4L in mice intestinal epithelium (Nedd4Lf/f;Vil-CreERT2) we show here that Nedd4L depletion leads to a higher steady-state short circuit current (Isc) in mouse distal colon tissue relative to controls...
January 13, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27940916/hierarchical-crmp2-posttranslational-modifications-control-nav1-7-function
#7
Erik T Dustrude, Aubin Moutal, Xiaofang Yang, Yuying Wang, May Khanna, Rajesh Khanna
Voltage-gated sodium channels are crucial determinants of neuronal excitability and signaling. Trafficking of the voltage-gated sodium channel NaV1.7 is dysregulated in neuropathic pain. We identify a trafficking program for NaV1.7 driven by hierarchical interactions with posttranslationally modified versions of the binding partner collapsin response mediator protein 2 (CRMP2). The binding described between CRMP2 and NaV1.7 was enhanced by conjugation of CRMP2 with small ubiquitin-like modifier (SUMO) and further controlled by the phosphorylation status of CRMP2...
December 27, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27825168/activation-of-sgk1-in-endometrial-epithelial-cells-in-response-to-pi3k-akt-inhibition-impairs-embryo-implantation
#8
Madhuri S Salker, Jennifer H Steel, Zohreh Hosseinzadeh, Jaya Nautiyal, Zoe Webster, Yogesh Singh, Sara Brucker, Florian Lang, Jan J Brosens
BACKGROUND: Serum & Glucocorticoid Regulated Kinase 1 (SGK1) plays a fundamental role in ion and solute transport processes in epithelia. In the endometrium, down-regulation of SGK1 during the window of receptivity facilitates embryo implantation whereas expression of a constitutively active mutant in the murine uterus blocks implantation. METHODS/RESULTS: Here, we report that treatment of endometrial epithelial cells with specific inhibitors of the phosphoinositide 3-kinase (PI3K)/AKT activity pathway results in reciprocal activation of SGK1...
2016: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/27786273/the-nedd4-2-ndfip1-axis-is-a-negative-regulator-of-ige-mediated-mast-cell-activation
#9
Kwok Ho Yip, Natasha Kolesnikoff, Nicholas Hauschild, Lisa Biggs, Angel F Lopez, Stephen J Galli, Sharad Kumar, Michele A Grimbaldeston
Cross-linkage of the high-affinity immunoglobulin E (IgE) receptor (FcɛRI) on mast cells by antigen ligation has a critical role in the pathology of IgE-dependent allergic disorders, such as anaphylaxis and asthma. Restraint of intracellular signal transduction pathways that promote release of mast cell-derived pro-inflammatory mediators is necessary to dampen activation and restore homoeostasis. Here we show that the ligase Nedd4-2 and the adaptor Ndfip1 (Nedd4 family interacting protein 1) limit the intensity and duration of IgE-FcɛRI-induced positive signal transduction by ubiquitinating phosphorylated Syk, a tyrosine kinase that is indispensable for downstream FcɛRI signalosome activity...
October 27, 2016: Nature Communications
https://www.readbyqxmd.com/read/27742835/the-torc1-activated-proteins-p70s6k-and-grb10-regulate-il-4-signaling-and-m2-macrophage-polarization-by-modulating-phosphorylation-of-insulin-receptor-substrate-2
#10
Kristi J Warren, Xi Fang, Nagaraj M Gowda, Joshua J Thompson, Nicola M Heller
Lung M2 macrophages are regulators of airway inflammation, associated with poor lung function in allergic asthma. Previously, we demonstrated that IL-4-induced M2 gene expression correlated with tyrosine phosphorylation of the insulin receptor substrate-2 (IRS-2) in macrophages. We hypothesized that negative regulation of IRS-2 activity after IL-4 stimulation is dependent upon serine phosphorylation of IRS-2. Herein, we describe an inverse relationship between tyrosine phosphorylation (Tyr(P)) and serine phosphorylation (Ser(P)) of IRS-2 after IL-4 stimulation...
November 25, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27613056/using-alphascreen-%C3%A2-to-identify-small-molecule-inhibitors-targeting-a-conserved-host-pathogen-interaction
#11
Sisley Austin, Saïd Taouji, Eric Chevet, Harald Wodrich, Fabienne Rayne
AlphaScreen(®) is a technology particularly suitable for bi-molecular inhibitor screening assays, e.g. using protein-protein interactions with purified recombinant proteins. Each binding partner of the bi-molecular interaction is coupled either to donor or to acceptor beads. The technology is based on the quantifiable transfer of oxygen singlets from donor to acceptor microbeads brought together by a specific interaction between the partners. We identified the conserved interaction between WW domains of cellular ubiquitin ligases of the Nedd4 family and a short peptide motif (PPxY) present in several structural and non-structural viral proteins as a potential drug target...
2016: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27604420/nedd4-2-haploinsufficiency-causes-hyperactivity-and-increased-sensitivity-to-inflammatory-stimuli
#12
Sudhirkumar Yanpallewar, Ting Wang, Dawn C I Koh, Eros Quarta, Gianluca Fulgenzi, Lino Tessarollo
Nedd4-2 (NEDD4L in humans) is a ubiquitin protein ligase best known for its role in regulating ion channel internalization and turnover. Nedd4-2 deletion in mice causes perinatal lethality associated with increased epithelial sodium channel (ENaC) expression in lung and kidney. Abundant data suggest that Nedd4-2 plays a role in neuronal functions and may be linked to epilepsy and dyslexia in humans. We used a mouse model of Nedd4-2 haploinsufficiency to investigate whether an alteration in Nedd4-2 levels of expression affects general nervous system functions...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27592201/proanthocyanidins-block-aldosterone-dependent-up-regulation-of-cardiac-gamma-enac-and-nedd4-2-inactivation-via-sgk1
#13
Adrián Galiana-Simal, Elena Olivares-Álvaro, Mercedes Klett-Mingo, María Belén Ruiz-Roso, Sandra Ballesteros, Natalia de Las Heras, Peter J Fuller, Vicente Lahera, Beatriz Martín-Fernández
Aldosterone plays a central role in the development of cardiac pathological states involving ion transport imbalances, especially sodium transport. We have previously demonstrated a cardioprotective effect of proanthocyanidins in aldosterone-treated rats. Our objective was to investigate for the first time the effect of proanthocyanidins on serum and glucocorticoid-regulated kinase 1 (SGK1), epithelial Na(+) channel (γ-ENaC), neuronal precursor cells expressed developmentally down-regulated 4-2 (Nedd4-2) and phosphoNedd4-2 protein expression in the hearts of aldosterone-treated rats...
August 14, 2016: Journal of Nutritional Biochemistry
https://www.readbyqxmd.com/read/27562465/mechanistic-target-of-rapamycin-mtor-regulates-trophoblast-folate-uptake-by-modulating-the-cell-surface-expression-of-fr-%C3%AE-and-the-rfc
#14
Fredrick J Rosario, Theresa L Powell, Thomas Jansson
Folate deficiency in fetal life is strongly associated with structural malformations and linked to intrauterine growth restriction. In addition, limited availability of methyl donors, such as folate, during pregnancy may result in abnormal gene methylation patterns and contribute to developmental programming. The fetus is dependent on placental transfer of folate, however the molecular mechanisms regulating placental folate transport are unknown. We used cultured primary human trophoblast cells to test the hypothesis that mechanistic target of rapamycin complex 1 (mTORC1) and 2 (mTORC2) regulate folate transport by post-translational mechanisms...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27462458/regulation-of-the-divalent-metal-ion-transporter-via-membrane-budding
#15
KimberlyD Mackenzie, Natalie J Foot, Sushma Anand, Hazel E Dalton, Natasha Chaudhary, Brett M Collins, Suresh Mathivanan, Sharad Kumar
The release of extracellular vesicles (EVs) is important for both normal physiology and disease. However, a basic understanding of the targeting of EV cargoes, composition and mechanism of release is lacking. Here we present evidence that the divalent metal ion transporter (DMT1) is unexpectedly regulated through release in EVs. This process involves the Nedd4-2 ubiquitin ligase, and the adaptor proteins Arrdc1 and Arrdc4 via different budding mechanisms. We show that mouse gut explants release endogenous DMT1 in EVs...
2016: Cell Discovery
https://www.readbyqxmd.com/read/27445338/ubiquitin-specific-protease-36-usp36-controls-neuronal-precursor-cell-expressed-developmentally-down-regulated-4-2-nedd4-2-actions-over-the-neurotrophin-receptor-trka-and-potassium-voltage-gated-channels-7-2-3-kv7-2-3
#16
Begoña Anta, Carlos Martín-Rodríguez, Carolina Gomis-Perez, Laura Calvo, Saray López-Benito, Andrés A Calderón-García, Cristina Vicente-García, Álvaro Villarroel, Juan C Arévalo
Ubiquitination of the TrkA neurotrophin receptor in response to NGF is critical in the regulation of TrkA activation and functions. TrkA is ubiquitinated, among other E3 ubiquitin ligases, by Nedd4-2. To understand mechanistically how TrkA ubiquitination is regulated, we performed a siRNA screening to identify deubiquitinating enzymes and found that USP36 acts as an important regulator of TrkA activation kinetics and ubiquitination. However, USP36 action on TrkA was indirect because it does not deubiquitinate TrkA...
September 2, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27409837/the-eif2%C3%AE-serine-51-phosphorylation-atf4-arm-promotes-hippo-signaling-and-cell-death-under-oxidative-stress
#17
Kamindla Rajesh, Jothilatha Krishnamoorthy, Jyotsana Gupta, Urszula Kazimierczak, Andreas I Papadakis, Zhilin Deng, Shuo Wang, Shinji Kuninaka, Antonis E Koromilas
The HIPPO pathway is an evolutionary conserved regulator of organ size that controls both cell proliferation and death. This pathway has an important role in mediating cell death in response to oxidative stress through the inactivation of Yes-associated protein (YAP) and inhibition of anti-oxidant gene expression. Cells exposed to oxidative stress induce the phosphorylation of the alpha (α) subunit of the translation initiation factor eIF2 at serine 51 (eIF2αP), a modification that leads to the general inhibition of mRNA translation initiation...
9, 2016: Oncotarget
https://www.readbyqxmd.com/read/27378758/chapter-five-ubiquitination-of-ion-channels-and-transporters
#18
S M Lamothe, S Zhang
Ion channels and transporters play essential roles in excitable cells including cardiac, skeletal, and smooth muscle cells, neurons, and endocrine cells. Their dysfunction underlies the pathology of various diseases. Thus, the tight regulation of these transmembrane proteins is essential for cell physiology. While the ubiquitin system is involved in many aspects of cellular processes, this chapter focuses on the ubiquitin-mediated degradation of ion channels and transporters. Ubiquitination of ion channels and transporters is multifaceted and occurs at various cellular compartments such as the plasma membrane and the endoplasmic reticulum...
2016: Progress in Molecular Biology and Translational Science
https://www.readbyqxmd.com/read/27256588/an-isoform-of-nedd4-2-is-critically-involved-in-the-renal-adaptation-to-high-salt-intake-in-mice
#19
Shintaro Minegishi, Tomoaki Ishigami, Tabito Kino, Lin Chen, Rie Nakashima-Sasaki, Naomi Araki, Keisuke Yatsu, Megumi Fujita, Satoshi Umemura
Epithelial sodium channels (ENaCs) play critical roles in the maintenance of fluid and electrolyte homeostasis, and their genetic abnormalities cause one type of hereditary salt-sensitive hypertension, Liddle syndrome. As we reported previously, both human and rodent Nedd4L/Nedd4-2 showed molecular diversity, with and without a C2 domain in their N-terminal. Nedd4L/Nedd4-2 isoforms with a C2 domain are hypothesized to be related closely to ubiquitination of ENaCs. We generated Nedd4-2 C2 domain knockout mice...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27146988/ubiquitin-ligase-nedd4-2-modulates-kv1-3-current-amplitude-and-ion-channel-protein-targeting
#20
Patricio Vélez, Austin B Schwartz, Subashini R Iyer, Anthony Warrington, Debra Ann Fadool
Voltage-dependent potassium channels (Kv) go beyond the stabilization of the resting potential and regulate biochemical pathways, regulate intracellular signaling, and detect energy homeostasis. Because targeted deletion and pharmacological block of the Kv1.3 channel protein produce marked changes in metabolism, resistance to diet-induced obesity, and changes in olfactory structure and function, this investigation explored Nedd4-2-mediated ubiquitination and degradation to regulate Kv1.3 channel density. Heterologous coexpression of Nedd4-2 ligase and Kv1...
August 1, 2016: Journal of Neurophysiology
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