Lafora disease ubiquitin ligase malin promotes proteasomal degradation of neuronatin and regulates glycogen synthesis

2011 ◽  
Vol 44 (1) ◽  
pp. 133-141 ◽  
Author(s):  
Jaiprakash Sharma ◽  
Sudheendra N.R. Rao ◽  
Susarla Krishna Shankar ◽  
Parthasarathy Satishchandra ◽  
Nihar Ranjan Jana
Keyword(s):  
Ubiquitin Ligase ◽  
Glycogen Synthesis ◽  
Proteasomal Degradation ◽  
Lafora Disease

scholarly journals Deficiency of the E3 Ubiquitin Ligase RBCK1 Causes Diffuse Brain Polyglucosan Accumulation and Neurodegeneration

2018 ◽  
Author(s):  
Mitchell A. Sullivan ◽  
Felix Nitschke ◽  
Erin E. Chown ◽  
Laura F. DiGiovanni ◽  
Mackenzie Chown ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
E3 Ubiquitin Ligase ◽  
Branching Enzyme ◽  
Lafora Disease ◽  
Ubiquitin Chain ◽  
Polyglucosan Bodies ◽  
Muscle Tissues ◽  
Neurobehavioral Deficits

SUMMARYGlycogen synthesis is vital, malstructure resulting in precipitation and accumulation into neurotoxic polyglucosan bodies (PBs). One well-understood mechanism of PB generation is glycogen branching enzyme deficiency (GBED). Less understood is Lafora disease (LD), resulting from absence of the glycogen phosphatase laforin or the E3 ubiquitin ligase malin, and accumulation of hyperphosphorylated PBs. LD afforded first insight that glycogen sphericity depends on more than adequate branching activity. Unexpectedly, deficiencies of the Linear Ubiquitin Chain Assembly Complex (LUBAC) components RBCK1 and HOIP result in PBs in muscle tissues. Here we analyzed nervous system phenotypes of mice lacking RBCK1 and find profuse PB accumulations in brain and spinal cord with extensive neurodegeneration and neurobehavioral deficits. Brain glycogen in these mice is characterized by long chains and hyperphosphorylation, similar to LD. Like in LD, glycogen synthase and branching enzyme are unaltered. Regional PB distribution mirrors LD and not GBED. Perisynaptic PB localization is unlike LD or GBED. The results indicate that RBCK1 is part of a system supplementing laforin-malin in regulating glycogen architecture including in unique neuronal locales.

scholarly journals Lafora Disease: A Review of Molecular Mechanisms and Pathology

2018 ◽  
Vol 49 (06) ◽  
pp. 357-362 ◽  
Author(s):  
Brandy Verhalen ◽  
Susan Arnold ◽  
Berge Minassian
Keyword(s):  
Ubiquitin Ligase ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Vegetative State ◽  
Glycogen Synthesis ◽  
Loss Of Function ◽  
Lafora Disease ◽  
Lafora Bodies ◽  
Progressive Myoclonus Epilepsy ◽  
Myoclonus Epilepsy

AbstractLafora's disease is a neurodegenerative disorder caused by recessive loss-of-function mutations in the EPM2A (laforin glycogen phosphatase) or EPM2B (malin E3 ubiquitin ligase) genes. Neuropathology is characterized by malformed precipitated glycogen aggregates termed Lafora bodies. Asymptomatic until adolescence, patients undergo first insidious then rapid progressive myoclonus epilepsy toward a vegetative state and death within a decade. Laforin and malin interact to regulate glycogen phosphorylation and chain length pattern, the latter critical to glycogen's solubility. Significant gaps remain in precise mechanistic understanding. However, demonstration that partial reduction in brain glycogen synthesis near-completely prevents the disease in its genetic animal models opens a direct present path to therapy.

Abstract 085: CHIP: E3 Ubiquitin Ligase Mediates Proteasomal Degradation of Neuronal Nitric Oxide Synthase in the Paraventricular Nucleus of Rats with Heart Failure

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Neeru M Sharma ◽  
Kenichi Katsurada ◽  
Xuefei Liu ◽  
Kaushik P Patel
Keyword(s):  
Nitric Oxide ◽  
Heart Failure ◽  
Nitric Oxide Synthase ◽  
Paraventricular Nucleus ◽  
Ubiquitin Ligase ◽  
Protein A ◽  
Neuronal Nitric Oxide Synthase ◽  
Proteasomal Degradation ◽  
Oxide Synthase

The exaggerated sympathetic drive is a characteristic of heart failure (HF) due to reduced neuronal nitric oxide synthase (nNOS) within the paraventricular nucleus (PVN). Previously we have shown that there were increased accumulation of nNOS-ubiquitin (nNOS-Ub) conjugates in the PVN of rats with HF (1.0±0.05 Sham vs. 1.29±0.06 HF) due to the increased levels of PIN (a protein inhibitor of nNOS, known to dissociate nNOS dimers into monomers) (0.76±0.10 Sham vs. 1.12±0.09 HF) and decreased levels of tetrahydrobiopterin (BH4): a cofactor required for stabilization of nNOS dimers (0.62±0.02 Sham vs. 0.44±0.03 HF). We also showed that there is blunted nitric oxide-mediated inhibition of sympathetic tone via the PVN in HF. Here we examined whether CHIP(C-terminus of Hsp70 -interacting protein), a chaperone-dependent E3 ubiquitin-protein isopeptide ligase known to ubiquitylate Hsp90-chaperoned proteins could act as an ubiquitin ligase for nNOS in the PVN. Immunofluorescence studies revealed colocalization of nNOS and CHIP in the PVN indicating their possible interaction. CHIP expression was increased by 50% in the PVN of rats with HF(0.96±0.08 Sham vs.1.44±0.10* HF). It is shown that Hsp90 protects nNOS from ubiquitination while Hsp70 promotes the ubiquitination and degradation. We observed significant upregulation of Hsp70 (0.49±0.03 Sham vs. 0.65±0.02* HF) with a trend toward the decrease in Hsp90 expression (0.90±0.07 Sham vs. 0.71±0.06 HF). The opposing effects of the two chaperones could account for the increased CHIP-mediated ubiquitination and degradation of dysfunctional nNOS monomers in the PVN of rats with HF. Furthermore, neuronal NG108-15 cell line transfected with the pCMV3-CHIP-GFP spark (CHIP overexpression plasmid) showed approximately 74% increase in CHIP with concomitant 49% decrease in nNOS expression. In vitro ubiquitination assay in NG108 cells transfected with pCMV-(HA-Ub) 8 and pCMV3-CHIP-GFP spark plasmid reveal increased HA-Ub-nNOS conjugates (1.13 ± 0.09 Scramble vs. 1.65 ± 0.12* CHIP plasmid). Taken together, our results identify CHIP as an E3 ligase for ubiquitination of dysfunctional nNOS and CHIP expression is augmented during HF leading to increased proteasomal degradation of nNOS in the PVN.

The ubiquitin specific protease USP34 protects the ubiquitin ligase gp78 from proteasomal degradation

2019 ◽  
Vol 509 (2) ◽  
pp. 348-353 ◽  
Author(s):  
Hui Wang ◽  
Donghong Ju ◽  
Dhong-Hyo Kho ◽  
Huanjie Yang ◽  
Li Li ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Proteasomal Degradation ◽  
Specific Protease ◽  
Ubiquitin Specific Protease

E3 ubiquitin ligase HECW2 mediates the proteasomal degradation of HP1 isoforms

2018 ◽  
Vol 503 (4) ◽  
pp. 2478-2484 ◽  
Author(s):  
Vidhya Krishnamoorthy ◽  
Richa Khanna ◽  
Veena K. Parnaik
Keyword(s):  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Proteasomal Degradation

scholarly journals Inhibiting glycogen synthesis prevents lafora disease in a mouse model

2013 ◽  
pp. n/a-n/a ◽  
Author(s):  
Bartholomew A Pederson ◽  
Julie Turnbull ◽  
Jonathan R Epp ◽  
Staci A Weaver ◽  
Xiaochu Zhao ◽  
...  
Keyword(s):  
Mouse Model ◽  
Glycogen Synthesis ◽  
Lafora Disease

Dual regulation of transcription factor Nrf2 by Keap1 and by the combined actions of β-TrCP and GSK-3

2015 ◽  
Vol 43 (4) ◽  
pp. 611-620 ◽  
Author(s):  
John D. Hayes ◽  
Sudhir Chowdhry ◽  
Albena T. Dinkova-Kostova ◽  
Calum Sutherland
Keyword(s):  
Transcription Factor ◽  
Growth Factors ◽  
Ubiquitin Ligase ◽  
Molecular Mechanisms ◽  
Glycogen Synthase ◽  
Proteasomal Degradation ◽  
Regulation Of Transcription ◽  
Related Factor ◽  
Nrf2 Target Gene ◽  
The Stability

Nuclear factor-erythroid 2 p45 (NF-E2 p45)-related factor 2 (Nrf2) is a master regulator of redox homoeostasis that allows cells to adapt to oxidative stress and also promotes cell proliferation. In this review, we describe the molecular mechanisms by which oxidants/electrophilic agents and growth factors increase Nrf2 activity. In the former case, oxidants/electrophiles increase the stability of Nrf2 by antagonizing the ability of Kelch-like ECH-associated protein 1 (Keap1) to target the transcription factor for proteasomal degradation via the cullin-3 (Cul3)–RING ubiquitin ligase CRLKeap1. In the latter case, we speculate that growth factors increase the stability of Nrf2 by stimulating phosphoinositide 3-kinase (PI3K)−protein kinase B (PKB)/Akt signalling, which in turn results in inhibitory phosphorylation of glycogen synthase kinase-3 (GSK-3) and in doing so prevents the formation of a DSGIS motif-containing phosphodegron in Nrf2 that is recognized by the β-transducin repeat-containing protein (β-TrCP) Cul1-based E3 ubiquitin ligase complex SCFβ-TrCP. We present data showing that in the absence of Keap1, the electrophile tert-butyl hydroquinone (tBHQ) can stimulate Nrf2 activity and induce the Nrf2-target gene NAD(P)H:quinone oxidoreductase-1 (NQO1), whilst simultaneously causing inhibitory phosphorylation of GSK-3β at Ser9. Together, these observations suggest that tBHQ can suppress the ability of SCFβ-TrCP to target Nrf2 for proteasomal degradation by increasing PI3K−PKB/Akt signalling. We also propose a scheme that explains how other protein kinases that inhibit GSK-3 could stimulate induction of Nrf2-target genes by preventing formation of the DSGIS motif-containing phosphodegron in Nrf2.

scholarly journals SIP/CacyBP promotes autophagy by regulating levels of BRUCE/Apollon, which stimulates LC3-I degradation

2019 ◽  
Vol 116 (27) ◽  
pp. 13404-13413 ◽  
Author(s):  
Tian-Xia Jiang ◽  
Jiang-Bo Zou ◽  
Qian-Qian Zhu ◽  
Cui Hua Liu ◽  
Guang-Fei Wang ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Cultured Cells ◽  
Proteasomal Degradation ◽  
Related Protein ◽  
Topoisomerase Inhibitors ◽  
Autophagosome Formation ◽  
Recycling Endosome ◽  
Proteasome Activator ◽  
Apoptosis Protein ◽  
Autophagic Degradation

BRUCE/Apollon is a membrane-associated inhibitor of apoptosis protein that is essential for viability and has ubiquitin-conjugating activity. On initiation of apoptosis, the ubiquitin ligase Nrdp1/RNF41 promotes proteasomal degradation of BRUCE. Here we demonstrate that BRUCE together with the proteasome activator PA28γ causes proteasomal degradation of LC3-I and thus inhibits autophagy. LC3-I on the phagophore membrane is conjugated to phosphatidylethanolamine to form LC3-II, which is required for the formation of autophagosomes and selective recruitment of substrates. SIP/CacyBP is a ubiquitination-related protein that is highly expressed in neurons and various tumors. Under normal conditions, SIP inhibits the ubiquitination and degradation of BRUCE, probably by blocking the binding of Nrdp1 to BRUCE. On DNA damage by topoisomerase inhibitors, Nrdp1 causes monoubiquitination of SIP and thus promotes apoptosis. However, on starvation, SIP together with Rab8 enhances the translocation of BRUCE into the recycling endosome, formation of autophagosomes, and degradation of BRUCE by optineurin-mediated autophagy. Accordingly, deletion of SIP in cultured cells reduces the autophagic degradation of damaged mitochondria and cytosolic protein aggregates. Thus, by stimulating proteasomal degradation of LC3-I, BRUCE also inhibits autophagy. Conversely, SIP promotes autophagy by blocking BRUCE-dependent degradation of LC3-I and by enhancing autophagosome formation and autophagic destruction of BRUCE. These actions of BRUCE and SIP represent mechanisms that link the regulation of autophagy and apoptosis under different conditions.

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