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 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 NOD1 is super-activated through spatially-selective ubiquitination by the Salmonella effector SspH2

2021 ◽  
Author(s):  
Cole Delyea ◽  
Shu Luo ◽  
Bradley E Dubrule ◽  
Olivier Julien ◽  
Amit P Bhavsar
Keyword(s):  
Mass Spectrometry ◽  
Ubiquitin Ligase ◽  
Inflammatory Cytokine ◽  
E3 Ubiquitin Ligase ◽  
Cytokine Secretion ◽  
Host Cells ◽  
List Type ◽  
The Novel ◽  
Inflammatory Signaling ◽  
Lysine Residues

As part of its pathogenesis, Salmonella enterica serovar Typhimurium delivers effector proteins into host cells. One effector is SspH2, a member of the novel E3 ubiquitin ligase family, interacts with, and enhances, NOD1 pro-inflammatory signaling, though the underlying mechanisms are unclear. Here, we report the novel discovery that SspH2 interacts with multiple members of the NLRC family to enhance pro-inflammatory signaling that results from targeted ubiquitination. We show that SspH2 modulates host innate immunity by interacting with both NOD1 and NOD2 in mammalian epithelial cell culture. We also show that SspH2 specifically interacts with the NBD and LRR domains of NOD1 and super-activates NOD1- and NOD2-mediated cytokine secretion via the NF-κB pathway. Mass spectrometry analyses identified lysine residues in NOD1 that were ubiquitinated after interaction with SspH2. Through NOD1 mutational analyses, we identified four key lysine residues that are required for NOD1 super-activation by SspH2, but not its basal activity. These critical lysine residues are positioned in the same region of NOD1 and define a surface on NOD1 that is targeted by SspH2. Overall, this work provides evidence for post-translational modification of NOD1 by ubiquitin, and uncovers a unique mechanism of spatially-selective ubiquitination to enhance the activation of an archetypal NLR.

scholarly journals Functional diversification of Ser-Arg rich protein kinases to control ubiquitin-dependent neurodevelopmental signalling

2020 ◽  
Author(s):  
Francisco Bustos ◽  
Anna Segarra-Fas ◽  
Gino Nardocci ◽  
Andrew Cassidy ◽  
Odetta Antico ◽  
...  
Keyword(s):  
Gene Expression ◽  
Intellectual Disability ◽  
Protein Kinases ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Point Mutations ◽  
Embryonic Stem ◽  
Mrna Splicing ◽  
Cellular Functions ◽  
Functional Diversification

SUMMARYConserved protein kinases with core cellular functions have been frequently redeployed during metazoan evolution to regulate specialized developmental processes. Ser-Arg Repeat Protein Kinase (SRPK) is one such conserved eukaryotic kinase, which controls mRNA splicing. Surprisingly, we show that SRPK has acquired a novel function in regulating a neurodevelopmental ubiquitin signalling pathway. In mammalian embryonic stem cells, SRPK phosphorylates Ser-Arg motifs in RNF12/RLIM, a key developmental E3 ubiquitin ligase that is mutated in an intellectual disability syndrome. Processive phosphorylation by SRPK stimulates RNF12-dependent ubiquitylation of transcription factor substrates, thereby acting to restrain a neural gene expression programme that is aberrantly expressed in intellectual disability. SRPK family genes are also mutated in intellectual disability disorders, and patient-derived SRPK point mutations impair RNF12 phosphorylation. Our data reveal unappreciated functional diversification of SRPK to regulate ubiquitin signalling that ensures correct regulation of neurodevelopmental gene expression.

scholarly journals The Molecular and Pathophysiological Functions of Members of the LNX/PDZRN E3 Ubiquitin Ligase Family

Molecules ◽  
2020 ◽  
Vol 25 (24) ◽  
pp. 5938
Author(s):  
Jeongkwan Hong ◽  
Minho Won ◽  
Hyunju Ro
Keyword(s):  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Ubiquitin Ligases ◽  
Ubiquitin Proteasome System ◽  
E3 Ubiquitin Ligases ◽  
Intercellular Signaling ◽  
Cellular Functions ◽  
Ring Type ◽  
Ubiquitin Ligase Activity ◽  
Ubiquitin Proteasome

The ligand of Numb protein-X (LNX) family, also known as the PDZRN family, is composed of four discrete RING-type E3 ubiquitin ligases (LNX1, LNX2, LNX3, and LNX4), and LNX5 which may not act as an E3 ubiquitin ligase owing to the lack of the RING domain. As the name implies, LNX1 and LNX2 were initially studied for exerting E3 ubiquitin ligase activity on their substrate Numb protein, whose stability was negatively regulated by LNX1 and LNX2 via the ubiquitin-proteasome pathway. LNX proteins may have versatile molecular, cellular, and developmental functions, considering the fact that besides these proteins, none of the E3 ubiquitin ligases have multiple PDZ (PSD95, DLGA, ZO-1) domains, which are regarded as important protein-interacting modules. Thus far, various proteins have been isolated as LNX-interacting proteins. Evidence from studies performed over the last two decades have suggested that members of the LNX family play various pathophysiological roles primarily by modulating the function of substrate proteins involved in several different intracellular or intercellular signaling cascades. As the binding partners of RING-type E3s, a large number of substrates of LNX proteins undergo degradation through ubiquitin-proteasome system (UPS) dependent or lysosomal pathways, potentially altering key signaling pathways. In this review, we highlight recent and relevant findings on the molecular and cellular functions of the members of the LNX family and discuss the role of the erroneous regulation of these proteins in disease progression.

scholarly journals Mechanism and disease association of E2-conjugating enzymes: lessons from UBE2T and UBE2L3

2016 ◽  
Vol 473 (20) ◽  
pp. 3401-3419 ◽  
Author(s):  
Arno F. Alpi ◽  
Viduth Chaugule ◽  
Helen Walden
Keyword(s):  
Ubiquitin Ligase ◽  
Severe Disease ◽  
Chromosome Instability ◽  
E3 Ubiquitin Ligase ◽  
Regulatory System ◽  
Disease Association ◽  
Cellular Functions ◽  
Disease States ◽  
Ubiquitin Binding

Ubiquitin signalling is a fundamental eukaryotic regulatory system, controlling diverse cellular functions. A cascade of E1, E2, and E3 enzymes is required for assembly of distinct signals, whereas an array of deubiquitinases and ubiquitin-binding modules edit, remove, and translate the signals. In the centre of this cascade sits the E2-conjugating enzyme, relaying activated ubiquitin from the E1 activating enzyme to the substrate, usually via an E3 ubiquitin ligase. Many disease states are associated with dysfunction of ubiquitin signalling, with the E3s being a particular focus. However, recent evidence demonstrates that mutations or impairment of the E2s can lead to severe disease states, including chromosome instability syndromes, cancer predisposition, and immunological disorders. Given their relevance to diseases, E2s may represent an important class of therapeutic targets. In the present study, we review the current understanding of the mechanism of this important family of enzymes, and the role of selected E2s in disease.

scholarly journals Topoisomerase 3B (TOP3B) DNA and RNA Cleavage Complexes and Pathway to Repair TOP3B-linked RNA and DNA Breaks

2020 ◽  
Author(s):  
Sourav Saha ◽  
Yilun Sun ◽  
Shar-Yin Huang ◽  
Ukhyun Jo ◽  
Hongliang Zhang ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Dna Cleavage ◽  
E3 Ubiquitin Ligase ◽  
Proteasomal Degradation ◽  
List Type ◽  
Dna Breaks ◽  
Dna And Rna ◽  
Self Trapping ◽  
Rna And Dna

SUMMARYGenetic inactivation of TOP3B is linked with schizophrenia, autism, intellectual disability and cancer. The present study demonstrates that in vivo TOP3B forms both RNA and DNA cleavage complexes (TOP3Bccs) and reveals a pathway for repairing TOP3Bccs. For detecting cellular TOP3Bccs, we engineered a “self-trapping” mutant of TOP3B (R338W TOP3B) and to determine how human cells repair TOP3Bccs, we depleted tyrosyl-DNA phosphodiesterases (TDP1 and TDP2). TDP2-deficient cells produced elevated TOP3Bccs both in DNA and RNA. Conversely, overexpression of TDP2 lowered cellular TOP3Bccs. Using recombinant human TDP2, we demonstrate that TDP2 cannot excise the native form of TOP3Bccs. Hypothesizing that TDP2 cannot access phosphotyrosyl linkage unless TOP3B is either proteolyzed or denatured, we found that cellular TOP3Bccs are ubiquitinated by the E3 Ubiquitin Ligase TRIM41 before undergoing proteasomal degradation and excision by TDP2.HIGHLIGHTSMethod for in vivo detection of TOP3B cleavage complexes (TOP3Bccs) formed both in DNA and RNA, using a religation defective “self-trapping” R338W TOP3B mutant.First evidence that TDP2 excises TOPccs produced by a type IA topoisomerase.TDP2 processes both RNA and DNA TOP3Bccs following their ubiquitylation and proteasomal degradation inside cell.TRIM41 is the first reported E3 ubiquitin ligase for TOP3Bcc ubiquitylation and proteasomal degradation.

scholarly journals Ubiquitin-dependent regulation of immune and inflammatory signaling pathways

2014 ◽  
Vol 70 (a1) ◽  
pp. C241-C241
Author(s):  
Katrin Rittinger
Keyword(s):  
Signaling Pathways ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
High Specificity ◽  
Cellular Functions ◽  
Inflammatory Signaling ◽  
Ubiquitin Chain ◽  
E3 Ligases ◽  
Wide Range ◽  
Chain Synthesis

Modification of proteins with ubiquitin is a key mechanism for the regulation of a wide range of cellular functions. The outcome of the modification is determined by the way ubiquitin molecules are linked to each other. Linear (M1-linked) ubiquitin chains play an important role in the regulation of immune and inflammatory signaling pathways and contribute to the activation of NF-κB. They are synthesized by the E3 ubiquitin ligase LUBAC (linear ubiquitin chain assembly complex) that is composed of at least three subunits named HOIL-1L, HOIP and SHARPIN. LUBAC belongs to the RBR (RING-inbetween-RING) family of E3 ligases that combine the properties of RING and HECT ligases and act as RING/HECT hybrids. Indeed, we have recently shown that linear ubiquitin chain synthesis proceeds via ubiquitin thioester intermediate formed by the HOIP subunit before subsequent transfer onto the target. I will present a combination of structural and biochemical data that provide a molecular explanation how this unusual E3 ligase complex promotes the synthesis of linear ubiquitin chains with high specificity, regardless of the E2 conjugating enzyme it works with.

scholarly journals ER-embedded UBE2J1/RNF26 ubiquitylation complex in spatiotemporal control of the endolysosomal pathway

2020 ◽  
Author(s):  
Tom Cremer ◽  
Marlieke L.M. Jongsma ◽  
Fredrik Trulsson ◽  
Alfred C.O. Vertegaal ◽  
Jacques J.C. Neefjes ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Cell Periphery ◽  
Perinuclear Region ◽  
Cellular Activity ◽  
Cellular Functions ◽  
Transport Dynamics ◽  
Ubiquitin Conjugating Enzyme ◽  
Spatiotemporal Control ◽  
Conjugating Enzyme

AbstractThe endolysosomal system fulfills a wide variety of cellular functions, many of which are modulated through interactions with other organelles. In particular, the ER exerts spatiotemporal constraints on the organization and motility of endosomes and lysosomes. We have recently described the ER transmembrane E3 ubiquitin ligase RNF26 to control perinuclear positioning and transport dynamics of the endolysosomal vesicular network. We now report that the ubiquitin conjugating enzyme UBE2J1, also anchored in the ER membrane, collaborates with RNF26 in this context, and that the cellular activity of this E2/E3 pair, localized in a perinuclear ER subdomain, is underpinned by transmembrane interactions. Through modification of its substrate SQSTM1/p62, the ER-embedded UBE2J1/RNF26 ubiquitylation complex recruits endosomal adaptors to immobilize their cognate vesicles in the perinuclear region. The resulting spatiotemporal compartmentalization of the endolysosomal system between the perinuclear vesicle cloud and the cell periphery facilitates timely downregulation of endocytosed cargoes, such as EGFR.

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