scholarly journals Regulation of synaptic growth and maturation by a synapse-associated E3 ubiquitin ligase at the neuromuscular junction

2007 ◽  
Vol 177 (6) ◽  
pp. 1077-1089 ◽  
Author(s):  
Zhonghua Lu ◽  
Hyun-Soo Je ◽  
Paul Young ◽  
Jimmy Gross ◽  
Bai Lu ◽  
...  
Keyword(s):  
Neuromuscular Junction ◽  
Ubiquitin Ligase ◽  
Dynamic Control ◽  
Pdz Domain ◽  
E3 Ubiquitin Ligase ◽  
Ring Finger ◽  
Surface Expression ◽  
Loss Of Function ◽  
Synaptic Development ◽  
Synaptic Growth

The ubiquitin–proteasome pathway has been implicated in synaptic development and plasticity. However, mechanisms by which ubiquitination contributes to precise and dynamic control of synaptic development and plasticity are poorly understood. We have identified a PDZ domain containing RING finger 3 (PDZRN3) as a synapse-associated E3 ubiquitin ligase and have demonstrated that it regulates the surface expression of muscle-specific receptor tyrosine kinase (MuSK), the key organizer of postsynaptic development at the mammalian neuromuscular junction. PDZRN3 binds to MuSK and promotes its ubiquitination. Regulation of cell surface levels of MuSK by PDZRN3 requires the ubiquitin ligase domain and is mediated by accelerated endocytosis. Gain- and loss-of-function studies in cultured myotubes show that regulation of MuSK by PDZRN3 plays an important role in MuSK-mediated nicotinic acetylcholine receptor clustering. Furthermore, overexpression of PDZRN3 in skeletal muscle of transgenic mice perturbs the growth and maturation of the neuromuscular junction. These results identify a synapse-associated E3 ubiquitin ligase as an important regulator of MuSK signaling.

scholarly journals Antagonistic Regulation of Circadian Output and Synaptic Development by the E3 Ubiquitin Ligase JETLAG and the DYSCHRONIC-SLOWPOKE Complex

2019 ◽  
Author(s):  
Angelique Lamaze ◽  
James E.C Jepson ◽  
Oghenerukevwe Akpoghiran ◽  
Kyunghee Koh
Keyword(s):  
Neuromuscular Junction ◽  
Ubiquitin Ligase ◽  
Light Exposure ◽  
E3 Ubiquitin Ligase ◽  
List Type ◽  
Cellular Functions ◽  
Synaptic Development ◽  
Channel Expression ◽  
Pdz Protein ◽  
Larval Neuromuscular Junction

SummaryCircadian output genes act downstream of the clock to promote rhythmic changes in behavior and physiology, yet their molecular and cellular functions are not well understood. Here we characterize an interaction between regulators of circadian entrainment, output and synaptic development in Drosophila that influences clock-driven anticipatory increases in morning and evening activity. We previously showed the JETLAG (JET) E3 Ubiquitin ligase resets the clock upon light exposure, while the PDZ protein DYSCHRONIC (DYSC) regulates circadian locomotor output and synaptic development. Surprisingly, we find that JET and DYSC antagonistically regulate synaptic development at the larval neuromuscular junction, and reduced JET activity rescues arrhythmicity of dysc mutants. Consistent with our prior finding that DYSC regulates SLOWPOKE (SLO) potassium channel expression, jet mutations also rescue circadian and synaptic phenotypes in slo mutants. Collectively, our data suggest that JET, DYSC and SLO promote circadian output in part by regulating synaptic morphology.HighlightsLoss of DYSC differentially impacts morning and evening oscillatorsReduced JET activity rescues the dysc and slo arrhythmic phenotypeReduced JET activity causes synaptic defects at the larval NMJJET opposes DYSC and SLO function at the NMJ synapse

scholarly journals The E3 Ubiquitin Ligase Mindbomb1 controls zebrafish Planar Cell Polarity

2021 ◽  
Author(s):  
Vishnu Muraleedharan Saraswathy ◽  
Priyanka Sharma ◽  
Akshai Janardhana Kurup ◽  
Sophie Polès ◽  
Morgane Poulain ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Cell Polarity ◽  
Ubiquitin Ligase ◽  
Protein Trafficking ◽  
Planar Cell Polarity ◽  
E3 Ubiquitin Ligase ◽  
Notch Pathway ◽  
Ring Finger ◽  
Critical Event ◽  
Loss Of Function

Vertebrate Delta/Notch signaling involves multiple ligands, receptors and transcription factors. Delta endocytosis – a critical event for Notch activation – is however essentially controlled by the E3 Ubiquitin ligase Mindbomb1 (Mib1). Due to its position at a molecular bottleneck of the pathway, Mib1 inactivation is often used to inhibit Notch signaling. However, recent findings indicate that the importance of Mib1 extends beyond the Notch pathway. We report an essential role of Mib1 in Planar Cell Polarity (PCP). mib1 null mutants or morphants display impaired gastrulation stage Convergence Extension (CE) movements. Comparison of different mib1 mutants and functional rescue experiments indicate that Mib1 controls CE independently of Notch. In contrast, Mib1-dependent CE defects can be rescued using the PCP downstream mediator RhoA. Mib1 regulates CE through the RING Finger domains that have been implicated in substrate ubiquitination, suggesting that Mib1 may control PCP protein trafficking. Accordingly, we show that Mib1 controls the endocytosis of the PCP component Ryk and that Ryk internalization is required for CE. Numerous morphogenetic processes involve both Notch and PCP signaling. We show that Mib1, a known Notch signaling regulator, is also an essential PCP pathway component. Care should therefore be taken when interpreting Mib1 loss of function phenotypes.

scholarly journals Ubiquitin ligase LNX1 is a major regulator of glycine recapture by the presynaptic transporter GlyT2

2017 ◽  
Author(s):  
E Núñez ◽  
E Arribas-González ◽  
B López-Corcuera ◽  
C Aragón ◽  
J de Juan-Sanz
Keyword(s):  
Ubiquitin Ligase ◽  
Synaptic Vesicles ◽  
E3 Ubiquitin Ligase ◽  
Ring Finger ◽  
Sudden Infant Death ◽  
Limiting Current ◽  
Sudden Infant ◽  
Loss Of Function ◽  
First Time ◽  
Glycinergic Neurotransmission

ABSTRACTThe neuronal glycine transporter GlyT2 is an essential regulator of glycinergic neurotransmission that recaptures glycine in presynaptic terminals to facilitate quantal transmitter packaging in synaptic vesicles. Alterations in GlyT2 expression or activity result in lower cytosolic glycine levels, emptying glycinergic synaptic vesicles and impairing neurotransmission. Lack of glycinergic neurotransmission caused by GlyT2 loss-of-function mutations results in Hyperekplexia, a rare neurological disease characterized by generalized stiffness and motor alterations that may result in sudden infant death. Although the importance of GlyT2 in pathology is known, how this transporter is regulated at the molecular level is poorly understood, limiting current therapeutic strategies. Guided by an unbiased screening, we discovered that the E3 ubiquitin ligase Ligand of Numb protein X1 (LNX1) modulates the ubiquitination status of GlyT2. LNX1 ubiquitinates a cytoplasmic C-terminal lysine cluster in GlyT2 (K751, K773, K787 and K791) through its N-terminal RING-finger domain, and this process regulates the expression levels and transport activity of GlyT2 in neurons. These experiments reveal for the first time the identity of an E3 ubiquitin-ligase acting on GlyT2 and identify a novel regulatory mechanism by which neurons regulate GlyT2 expression and activity.

scholarly journals An E3 Ubiquitin Ligase RNF139 Serves as a Tumor-Suppressor in Glioma

2021 ◽  
Author(s):  
Xiaofeng Chen ◽  
Weiping Kuang ◽  
Yong Zhu ◽  
Bin Zhou ◽  
Xiaosong Li ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Cell Lines ◽  
Ubiquitin Ligase ◽  
Glioma Cell ◽  
Protein Modification ◽  
E3 Ubiquitin Ligase ◽  
Ring Finger ◽  
Glioma Cells ◽  
Migration And Invasion ◽  
Tissue Samples

AbstractGlioma is highly lethal because of its high malignancy. Ubiquitination, a type of ubiquitin-dependent protein modification, has been reported to play an oncogenic or tumor-suppressive role in glioma development, depending on the targets. Ring finger protein 139 (RNF139) is a membrane-bound E3 ubiquitin ligase serving as a tumor suppressor by ubiquitylation-dependently suppressing cell growth. Herein, we firstly confirmed the abnormal downregulation of RNF139 in glioma tissues and cell lines. In glioma cells, ectopic RNF139 overexpression could inhibit, whereas RNF139 knockdown could aggravate the aggressive behaviors of glioma cells, including hyperproliferation, migration, and invasion. Moreover, in two glioma cell lines, RNF139 overexpression inhibited, whereas RNF139 knockdown enhanced the phosphorylation of phosphatidylinositol 3-kinase (PI3K) and AKT serine/threonine kinase 1 (AKT). In a word, we demonstrate the aberration in RNF139 expression in glioma tissue samples and cell lines. RNF139 serves as a tumor-suppressor in glioma by inhibiting glioma cell proliferation, migration, and invasion and promoting glioma cell apoptosis through regulating PI3K/AKT signaling.

scholarly journals p53 down-regulates SARS coronavirus replication and is targeted by the SARS-unique domain and PLprovia E3 ubiquitin ligase RCHY1

2016 ◽  
Vol 113 (35) ◽  
pp. E5192-E5201 ◽  
Author(s):  
Yue Ma-Lauer ◽  
Javier Carbajo-Lozoya ◽  
Marco Y. Hein ◽  
Marcel A. Müller ◽  
Wen Deng ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Nonstructural Protein ◽  
E3 Ubiquitin Ligase ◽  
Ring Finger ◽  
Immune Recognition ◽  
Major Player ◽  
Nonstructural Protein 3 ◽  
Human Coronaviruses ◽  
Unique Domain

Highly pathogenic severe acute respiratory syndrome coronavirus (SARS-CoV) has developed strategies to inhibit host immune recognition. We identify cellular E3 ubiquitin ligase ring-finger and CHY zinc-finger domain-containing 1 (RCHY1) as an interacting partner of the viral SARS-unique domain (SUD) and papain-like protease (PLpro), and, as a consequence, the involvement of cellular p53 as antagonist of coronaviral replication. Residues 95–144 of RCHY1 and 389–652 of SUD (SUD-NM) subdomains are crucial for interaction. Association with SUD increases the stability of RCHY1 and augments RCHY1-mediated ubiquitination as well as degradation of p53. The calcium/calmodulin-dependent protein kinase II delta (CAMK2D), which normally influences RCHY1 stability by phosphorylation, also binds to SUD. In vivo phosphorylation shows that SUD does not regulate phosphorylation of RCHY1 via CAMK2D. Similarly to SUD, the PLpros from SARS-CoV, MERS-CoV, and HCoV-NL63 physically interact with and stabilize RCHY1, and thus trigger degradation of endogenous p53. The SARS-CoV papain-like protease is encoded next to SUD within nonstructural protein 3. A SUD–PLprofusion interacts with RCHY1 more intensively and causes stronger p53 degradation than SARS-CoV PLproalone. We show that p53 inhibits replication of infectious SARS-CoV as well as of replicons and human coronavirus NL63. Hence, human coronaviruses antagonize the viral inhibitor p53 via stabilizing RCHY1 and promoting RCHY1-mediated p53 degradation. SUD functions as an enhancer to strengthen interaction between RCHY1 and nonstructural protein 3, leading to a further increase in in p53 degradation. The significance of these findings is that down-regulation of p53 as a major player in antiviral innate immunity provides a long-sought explanation for delayed activities of respective genes.

Abstract 18: Synoviolin, an E3 Ubiquitin Ligase, Modulates Cardiac Myocyte Size and Restores Heart Function in Hypertrophic Cardiomyopathy

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Shirin Doroudgar ◽  
Mirko Völkers ◽  
Donna J Thuerauf ◽  
Ashley Bumbar ◽  
Mohsin Khan ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Protein Misfolding ◽  
Cardiac Myocyte ◽  
Protein Quality ◽  
Heart Function ◽  
E3 Ubiquitin Ligase ◽  
Ubiquitin Ligases ◽  
Calcium Handling ◽  
Loss Of Function

The endoplasmic reticulum (ER) is essential for protein homeostasis, or proteostasis, which governs the balance of the proteome. In addition to secreted and membrane proteins, proteins bound for many other cellular locations are also made on ER-bound ribosomes, emphasizing the importance of protein quality and quantity control in the ER. Unlike cytosolic E3 ubiquitin ligases studied in the heart, synoviolin/Hrd1, which has not been studied in the heart, is an ER transmembrane E3 ubiquitin ligase, which we found to be upregulated upon protein misfolding in cardiac myocytes. Given the strategic location of synoviolin in the ER membrane, we addressed the hypothesis that synoviolin is critical for regulating the balance of the proteome, and accordingly, myocyte size. We showed that in vitro, adenovirus-mediated overexpression of synoviolin decreased cardiac myocyte size and protein synthesis, but unlike atrophy-related ubiquitin ligases, synoviolin did not increase global protein degradation. Furthermore, targeted gene therapy using adeno-associated virus 9 (AAV9) showed that overexpression of synoviolin in the left ventricle attenuated maladaptive cardiac hypertrophy and preserved cardiac function in mice subjected to trans-aortic constriction (AAV9-control TAC = 22.5 ± 6.2% decrease in EF vs. AAV9-synoviolin TAC at 6 weeks post TAC; P<0.001), and decreased mTOR activity. Since calcium is a major regulator of cardiac myocyte size, we examined the effects of synoviolin gain- or loss-of-function, using AAV9-synoviolin, or an miRNA designed to knock down synoviolin, respectively. While synoviolin gain-of-function did not affect calcium handling in isolated adult myocytes, synoviolin loss-of-function increased calcium transient amplitude (P<0.01), prolonged spark duration (P<0.001), and increased spark width (P<0.001). Spark frequency and amplitude were unaltered upon synoviolin gain- or loss-of-function. Whereas SR calcium load was unaltered by synoviolin loss-of-function, SERCA-mediated calcium removal was reduced (P<0.05). In conclusion, our studies suggest that in the heart, synoviolin is 1) a critical component of proteostasis, 2) a novel determinant of cardiac myocyte size, and 3) necessary for proper calcium handling.

Apple RING finger E3 ubiquitin ligase MdMIEL1 negatively regulates salt and oxidative stresses tolerance

2017 ◽  
Vol 60 (2) ◽  
pp. 137-145 ◽  
Author(s):  
Jian-Ping An ◽  
Xin Liu ◽  
Lai-Qing Song ◽  
Chun-Xiang You ◽  
Xiao-Fei Wang ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Ring Finger ◽  
Oxidative Stresses ◽  
Salt And Oxidative Stresses
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