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 Proteomic analysis identifies the E3 ubiquitin ligase Pdzrn3 as a regulatory target of Wnt5a-Ror signaling

2021 ◽  
Vol 118 (25) ◽  
pp. e2104944118
Author(s):  
Sara E. Konopelski Snavely ◽  
Michael W. Susman ◽  
Ryan C. Kunz ◽  
Jia Tan ◽  
Srisathya Srinivasan ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Large Scale ◽  
Glycogen Synthase ◽  
E3 Ubiquitin Ligase ◽  
Ubiquitin Proteasome System ◽  
Dependent Manner ◽  
Casein Kinase 1 ◽  
Downstream Signaling ◽  
Proteomic Screen ◽  
Responsive Element

Wnt5a-Ror signaling is a conserved pathway that regulates morphogenetic processes during vertebrate development [R. T. Moon et al., Development 119, 97–111 (1993); I. Oishi et al., Genes Cells 8, 645–654 (2003)], but its downstream signaling events remain poorly understood. Through a large-scale proteomic screen in mouse embryonic fibroblasts, we identified the E3 ubiquitin ligase Pdzrn3 as a regulatory target of the Wnt5a-Ror pathway. Upon pathway activation, Pdzrn3 is degraded in a β-catenin–independent, ubiquitin-proteasome system–dependent manner. We developed a flow cytometry-based reporter to monitor Pdzrn3 abundance and delineated a signaling cascade involving Frizzled, Dishevelled, Casein kinase 1, and Glycogen synthase kinase 3 that regulates Pdzrn3 stability. Epistatically, Pdzrn3 is regulated independently of Kif26b, another Wnt5a-Ror effector. Wnt5a-dependent degradation of Pdzrn3 requires phosphorylation of three conserved amino acids within its C-terminal LNX3H domain [M. Flynn, O. Saha, P. Young, BMC Evol. Biol. 11, 235 (2011)], which acts as a bona fide Wnt5a-responsive element. Importantly, this phospho-dependent degradation is essential for Wnt5a-Ror modulation of cell migration. Collectively, this work establishes a Wnt5a-Ror cell morphogenetic cascade involving Pdzrn3 phosphorylation and degradation.

scholarly journals Linear Ubiquitination Mediates EGFR-Induced NF-κB Pathway and Tumor Development

2021 ◽  
Vol 22 (21) ◽  
pp. 11875
Author(s):  
Fang Hua ◽  
Wenzhuo Hao ◽  
Lingyan Wang ◽  
Shitao Li
Keyword(s):  
Cell Proliferation ◽  
Ubiquitin Ligase ◽  
Tumor Development ◽  
E3 Ubiquitin Ligase ◽  
Growth Factor Receptor ◽  
Ubiquitin Chain ◽  
Plakophilin 2 ◽  
Ubiquitin Ligase Activity ◽  
Signaling Axis ◽  
Differentiation And Proliferation

Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that instigates several signaling cascades, including the NF-κB signaling pathway, to induce cell differentiation and proliferation. Overexpression and mutations of EGFR are found in up to 30% of solid tumors and correlate with a poor prognosis. Although it is known that EGFR-mediated NF-κB activation is involved in tumor development, the signaling axis is not well elucidated. Here, we found that plakophilin 2 (PKP2) and the linear ubiquitin chain assembly complex (LUBAC) were required for EGFR-mediated NF-κB activation. Upon EGF stimulation, EGFR recruited PKP2 to the plasma membrane, and PKP2 bridged HOIP, the catalytic E3 ubiquitin ligase in the LUBAC, to the EGFR complex. The recruitment activated the LUBAC complex and the linear ubiquitination of NEMO, leading to IκB phosphorylation and subsequent NF-κB activation. Furthermore, EGF-induced linear ubiquitination was critical for tumor cell proliferation and tumor development. Knockout of HOIP impaired EGF-induced NF-κB activity and reduced cell proliferation. HOIP knockout also abrogated the growth of A431 epidermal xenograft tumors in nude mice by more than 70%. More importantly, the HOIP inhibitor, HOIPIN-8, inhibited EGFR-mediated NF-κB activation and cell proliferation of A431, MCF-7, and MDA-MB-231 cancer cells. Overall, our study reveals a novel linear ubiquitination signaling axis of EGFR and that perturbation of HOIP E3 ubiquitin ligase activity is potential targeted cancer therapy.

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 Lafora disease E3-ubiquitin ligase malin is related to TRIM32 at both the phylogenetic and functional level

2011 ◽  
Vol 11 (1) ◽  
Author(s):  
Carlos Romá-Mateo ◽  
Daniel Moreno ◽  
Santiago Vernia ◽  
Teresa Rubio ◽  
Travis M Bridges ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Lafora Disease ◽  
Functional Level

scholarly journals Targeting pathogenic Lafora bodies in Lafora disease using an antibody-enzyme fusion

2019 ◽  
Author(s):  
M. Kathryn Brewer ◽  
Annette Uittenbogaard ◽  
Grant Austin ◽  
John J. McCarthy ◽  
Dyann M. Segvich ◽  
...  
Keyword(s):  
Glycogen Synthesis ◽  
Intractable Epilepsy ◽  
Antibody Fragment ◽  
Glycogen Storage ◽  
Childhood Epilepsy ◽  
Lafora Disease ◽  
Polyglucosan Bodies ◽  
Lafora Bodies ◽  
Enzyme Fusion

AbstractLafora disease (LD) is a fatal childhood epilepsy and a non-classical glycogen storage disorder with no effective therapy or cure. LD is caused by recessive mutations in theEPM2AorEPM2Bgenes that encode the glycogen phosphatase laforin and an E3 ubiquitin ligase malin, respectively. A hallmark of LD is the intracellular accumulation of abnormal and insoluble α-linked polysaccharide deposits known as Lafora bodies (LBs) in several tissues, including most regions of the brain. In mouse models of LD, genetic reduction of glycogen synthesis eliminates LB formation and rescues the neurological phenotype. Since multiple groups have confirmed that neurodegeneration and epilepsy result from LB accumulation, a major focus in the field has shifted toward the development of therapies that reduce glycogen synthesis or target LBs for degradation with the goal of treating LD. Herein, we identify the optimal enzymes for degrading LBs, and we develop a novel therapeutic agent by fusing human pancreatic α-amylase to a cellpenetrating antibody fragment. This antibody-enzyme fusion (VAL-0417) degrades LBsin vitro, shows robust cellular uptake, and significantly reduces the LB loadin vivoinEpm2a-/- mice. VAL-0417 is a promising therapeutic for the treatment of LD and a putative precision therapy for an intractable epilepsy. Antibody-enzyme fusions represent a new class of antibody-based drugs that could be utilized to treat glycogen storage disorders and other diseases.One Sentence SummaryAn antibody-enzyme fusion delivering an amylase degrades the toxic polyglucosan bodies that cause Lafora disease, a fatal childhood epilepsy.

Structural basis of K63-ubiquitin chain formation by the Gordon-Holmes syndrome RBR E3 ubiquitin ligase RNF216

2022 ◽  
Author(s):  
Thomas R. Cotton ◽  
Simon A. Cobbold ◽  
Jonathan P. Bernardini ◽  
Lachlan W. Richardson ◽  
Xiangyi S. Wang ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Structural Basis ◽  
Ubiquitin Chain ◽  
Chain Formation

Astrocytic glycogen accumulation drives the pathophysiology of neurodegeneration in Lafora disease

Brain ◽  
2021 ◽  
Author(s):  
Jordi Duran ◽  
Arnau Hervera ◽  
Kia H Markussen ◽  
Olga Varea ◽  
Iliana López-Soldado ◽  
...  
Keyword(s):  
Mouse Model ◽  
Neurodegenerative Disorder ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Glycogen Metabolism ◽  
Cell Type ◽  
Lafora Disease ◽  
Glycogen Accumulation ◽  
Lafora Bodies

Abstract The hallmark of Lafora disease, a fatal neurodegenerative disorder, is the accumulation of intracellular glycogen aggregates, called Lafora bodies. Until recently, it was widely believed that brain Lafora bodies were present exclusively in neurons and thus that Lafora disease pathology derived from their accumulation in this cell population. However, recent evidence indicates that Lafora bodies are also present in astrocytes. To define the role of astrocytic Lafora bodies in Lafora disease pathology, we deleted glycogen synthase specifically from astrocytes in a mouse model of the disease (malinKO). Strikingly, blocking glycogen synthesis in astrocytes—thus impeding Lafora bodies accumulation in this cell type—prevented the increase in neurodegeneration markers, autophagy impairment, and metabolic changes characteristic of the malinKO model. Conversely, mice that overaccumulate glycogen in astrocytes showed an increase in these markers. These results unveil the deleterious consequences of the deregulation of glycogen metabolism in astrocytes and change the perspective that Lafora disease is caused solely by alterations in neurons.

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