scholarly journals Homeostatic scaling is driven by a translation-dependent degradation axis that recruits miRISC remodelling

2020 ◽  
Author(s):  
Balakumar Srinivasan ◽  
Sarbani Samaddar ◽  
Sivaram V.S. Mylavarapu ◽  
James P. Clement ◽  
Sourav Banerjee
Keyword(s):  
Ampa Receptors ◽  
26S Proteasome ◽  
Network Activity ◽  
Degradation Mechanisms ◽  
Subsequent Removal ◽  
Ternary Interaction ◽  
Synaptic Homeostasis ◽  
Subsequent Degradation ◽  
The Individual ◽  
Translational Apparatus

AbstractHomeostatic scaling in neurons has been majorly attributed to the individual contribution of either translation or degradation; however there remains limited insight towards understanding how the interplay between the two processes effectuates synaptic homeostasis. Here, we report that a co-dependence between the translation and degradation mechanisms drives synaptic homeostasis whereas abrogation of either prevents it. Coordination between the two processes is achieved through the formation of a tripartite complex between translation regulators, the 26S proteasome and the miRNA-induced-silencing-complex (miRISC) components such as MOV10 and Trim32 on actively translating transcripts or polysomes. Disruption of polysomes abolishes this ternary interaction, suggesting that translating RNAs facilitate the combinatorial action of the proteasome and the translational apparatus. We identify that synaptic downscaling involves miRISC remodelling which entails the mTOR-dependent translation of Trim32, an E3 ligase and the subsequent degradation of its target, MOV10. MOV10 degradation is sufficient to invoke downscaling by enhancing Arc expression and causing the subsequent removal of post-synaptic AMPA receptors. We propose a mechanism that exploits a translation-driven degradation paradigm to invoke miRISC remodelling and induce homeostatic scaling during chronic network activity.

scholarly journals Homeostatic scaling is driven by a translation-dependent degradation axis that recruits miRISC remodeling

PLoS Biology ◽  
2021 ◽  
Vol 19 (11) ◽  
pp. e3001432
Author(s):  
Balakumar Srinivasan ◽  
Sarbani Samaddar ◽  
Sivaram V. S. Mylavarapu ◽  
James P. Clement ◽  
Sourav Banerjee
Keyword(s):  
Ampa Receptors ◽  
E3 Ligase ◽  
26S Proteasome ◽  
Network Activity ◽  
Dependent Manner ◽  
Synaptic Homeostasis ◽  
Subsequent Degradation ◽  
The Individual ◽  
Translational Apparatus ◽  
Synthesis And Degradation

Homeostatic scaling in neurons has been attributed to the individual contribution of either translation or degradation; however, there remains limited insight toward understanding how the interplay between the two processes effectuates synaptic homeostasis. Here, we report that a codependence between protein synthesis and degradation mechanisms drives synaptic homeostasis, whereas abrogation of either prevents it. Coordination between the two processes is achieved through the formation of a tripartite complex between translation regulators, the 26S proteasome, and the miRNA-induced silencing complex (miRISC) components such as Argonaute, MOV10, and Trim32 on actively translating transcripts or polysomes. The components of this ternary complex directly interact with each other in an RNA-dependent manner. Disruption of polysomes abolishes this ternary interaction, suggesting that translating RNAs facilitate the combinatorial action of the proteasome and the translational apparatus. We identify that synaptic downscaling involves miRISC remodeling, which entails the mTORC1-dependent translation of Trim32, an E3 ligase, and the subsequent degradation of its target, MOV10 via the phosphorylation of p70 S6 kinase. We find that the E3 ligase Trim32 specifically polyubiquitinates MOV10 for its degradation during synaptic downscaling. MOV10 degradation alone is sufficient to invoke downscaling by enhancing Arc translation through its 3′ UTR and causing the subsequent removal of postsynaptic AMPA receptors. Synaptic scaling was occluded when we depleted Trim32 and overexpressed MOV10 in neurons, suggesting that the Trim32-MOV10 axis is necessary for synaptic downscaling. We propose a mechanism that exploits a translation-driven protein degradation paradigm to invoke miRISC remodeling and induce homeostatic scaling during chronic network activity.

scholarly journals Liposomal Encapsulated FSC231, a PICK1 Inhibitor, Prevents the Ischemia/Reperfusion-Induced Degradation of GluA2-Containing AMPA Receptors

Pharmaceutics ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 636
Author(s):  
Lindsay M. Achzet ◽  
Fanny Astruc-Diaz ◽  
Phillip H. Beske ◽  
Nicholas R. Natale ◽  
Travis T. Denton ◽  
...  
Keyword(s):  
Intracellular Calcium ◽  
Ampa Receptors ◽  
Research Effort ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
The United States ◽  
Excitatory Neurotransmitter ◽  
Protein Levels ◽  
Neurotransmitter Glutamate ◽  
Subsequent Degradation

Strokes remain one of the leading causes of disability within the United States. Despite an enormous amount of research effort within the scientific community, very few therapeutics are available for stroke patients. Cytotoxic accumulation of intracellular calcium is a well-studied phenomenon that occurs following ischemic stroke. This intracellular calcium overload results from excessive release of the excitatory neurotransmitter glutamate, a process known as excitotoxicity. Calcium-permeable AMPA receptors (AMPARs), lacking the GluA2 subunit, contribute to calcium cytotoxicity and subsequent neuronal death. The internalization and subsequent degradation of GluA2 AMPAR subunits following oxygen–glucose deprivation/reperfusion (OGD/R) is, at least in part, mediated by protein-interacting with C kinase-1 (PICK1). The purpose of the present study is to evaluate whether treatment with a PICK1 inhibitor, FSC231, prevents the OGD/R-induced degradation of the GluA2 AMPAR subunit. Utilizing an acute rodent hippocampal slice model system, we determined that pretreatment with FSC231 prevented the OGD/R-induced association of PICK1–GluA2. FSC231 treatment during OGD/R rescues total GluA2 AMPAR subunit protein levels. This suggests that the interaction between GluA2 and PICK1 serves as an important step in the ischemic/reperfusion-induced reduction in total GluA2 levels.

scholarly journals Role for Human SIRT2 NAD-Dependent Deacetylase Activity in Control of Mitotic Exit in the Cell Cycle

2003 ◽  
Vol 23 (9) ◽  
pp. 3173-3185 ◽  
Author(s):  
Sylvia C. Dryden ◽  
Fatimah A. Nahhas ◽  
James E. Nowak ◽  
Anton-Scott Goustin ◽  
Michael A. Tainsky
Keyword(s):  
Cell Cycle ◽  
Protein A ◽  
Proteasome Inhibitors ◽  
26S Proteasome ◽  
Functional Studies ◽  
Cellular Life ◽  
Subsequent Decrease ◽  
Subsequent Degradation ◽  
Phosphorylation Cascade ◽  
And Control

ABSTRACT Studies of yeast have shown that the SIR2 gene family is involved in chromatin structure, transcriptional silencing, DNA repair, and control of cellular life span. Our functional studies of human SIRT2, a homolog of the product of the yeast SIR2 gene, indicate that it plays a role in mitosis. The SIRT2 protein is a NAD-dependent deacetylase (NDAC), the abundance of which increases dramatically during mitosis and is multiply phosphorylated at the G2/M transition of the cell cycle. Cells stably overexpressing the wild-type SIRT2 but not missense mutants lacking NDAC activity show a marked prolongation of the mitotic phase of the cell cycle. Overexpression of the protein phosphatase CDC14B, but not its close homolog CDC14A, results in dephosphorylation of SIRT2 with a subsequent decrease in the abundance of SIRT2 protein. A CDC14B mutant defective in catalyzing dephosphorylation fails to change the phosphorylation status or abundance of SIRT2 protein. Addition of 26S proteasome inhibitors to human cells increases the abundance of SIRT2 protein, indicating that SIRT2 is targeted for degradation by the 26S proteasome. Our data suggest that human SIRT2 is part of a phosphorylation cascade in which SIRT2 is phosphorylated late in G2, during M, and into the period of cytokinesis. CDC14B may provoke exit from mitosis coincident with the loss of SIRT2 via ubiquitination and subsequent degradation by the 26S proteasome.

scholarly journals Jasmonate and auxin perception: how plants keep F-boxes in check

2019 ◽  
Vol 70 (13) ◽  
pp. 3401-3414 ◽  
Author(s):  
Clara Williams ◽  
Patricia Fernández-Calvo ◽  
Maite Colinas ◽  
Laurens Pauwels ◽  
Alain Goossens
Keyword(s):  
Protein Interactions ◽  
26S Proteasome ◽  
Protein Protein Interactions ◽  
Biotic And Abiotic Stresses ◽  
Post Translational Modifications ◽  
Receptor Complexes ◽  
Subsequent Degradation ◽  
Selective Agonists ◽  
Multiple Levels ◽  
Type Receptor

Abstract Phytohormones regulate the plasticity of plant growth and development, and responses to biotic and abiotic stresses. Many hormone signal transduction cascades involve ubiquitination and subsequent degradation of proteins by the 26S proteasome. The conjugation of ubiquitin to a substrate is facilitated by the E1 activating, E2 conjugating, and the substrate-specifying E3 ligating enzymes. The most prevalent type of E3 ligase in plants is the Cullin–RING ligase (CRL)-type, with F-box proteins (FBPs) as the substrate recognition component. The activity of these SKP–Cullin–F-box (SCF) complexes needs to be tightly regulated in time and place. Here, we review the regulation of SCF function in plants on multiple levels, with a focus on the auxin and jasmonate SCF-type receptor complexes. We discuss in particular the relevance of protein–protein interactions and post-translational modifications as mechanisms to keep SCF functioning under control. Additionally, we highlight the unique property of SCFTIR1/AFB and SCFCOI1 to recognize substrates by forming co-receptor complexes. Finally, we explore how engineered selective agonists can be used to study and uncouple the outcomes of the complex auxin and jasmonate signaling networks that are governed by these FBPs.

scholarly journals Characterization of Brassica rapa RAP2.4-Related Proteins in Stress Response and as CUL3-Dependent E3 Ligase Substrates

Cells ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 336 ◽  
Author(s):  
Sutton Mooney ◽  
Raed Al-Saharin ◽  
Christina M. Choi ◽  
Kyle Tucker ◽  
Chase Beathard ◽  
...  
Keyword(s):  
Brassica Rapa ◽  
Stress Responses ◽  
Expression Patterns ◽  
Economic Value ◽  
E3 Ligase ◽  
26S Proteasome ◽  
Dependent Manner ◽  
E3 Ligases ◽  
Subsequent Degradation ◽  
Stress Dependent

The turnip Brassica rapa has important economic value and represents a good model system to study gene function in crop plants. ERF/AP2 transcription factors are a major group of proteins that are often involved in regulating stress-responses and developmental programs. Some ERF/AP2 proteins are targets of CULLIN3-based E3 ligases that use BTB/POZ-MATH proteins as substrate receptors. These receptors bind the transcription factor and facilitate their ubiquitylation and subsequent degradation via the 26S proteasome. Here, we show tissue and stress-dependent expression patterns for three Brassica rapa ERF/AP2 proteins that are closely related to Arabidopsis thaliana AtRAP2.4. Cloning of the Brassica genes showed that the corresponding proteins can assemble with a BPM protein and CULLIN3, and that they are instable in a 26S proteasome dependent manner. This work demonstrates the conserved nature of the ERF/AP2-CULLIN3-based E3 ligase interplay, and represents a first step to analyze their function in a commercially relevant crop plant.

scholarly journals Ubiquitin–Proteasome-dependent Degradation of a Mitofusin, a Critical Regulator of Mitochondrial Fusion

2008 ◽  
Vol 19 (6) ◽  
pp. 2457-2464 ◽  
Author(s):  
Mickael M.J. Cohen ◽  
Guillaume P. Leboucher ◽  
Nurit Livnat-Levanon ◽  
Michael H. Glickman ◽  
Allan M. Weissman
Keyword(s):  
Mitochondrial Fusion ◽  
26S Proteasome ◽  
Mitochondrial Outer Membrane ◽  
Yeast Saccharomyces Cerevisiae ◽  
Subsequent Degradation ◽  
Multistep Process ◽  
Ubiquitin Proteasome ◽  
Steady State Levels ◽  
F Box Protein

The mitochondrion is a dynamic membranous network whose morphology is conditioned by the equilibrium between ongoing fusion and fission of mitochondrial membranes. In the budding yeast, Saccharomyces cerevisiae, the transmembrane GTPase Fzo1p controls fusion of mitochondrial outer membranes. Deletion or overexpression of Fzo1p have both been shown to alter the mitochondrial fusion process indicating that maintenance of steady-state levels of Fzo1p are required for efficient mitochondrial fusion. Cellular levels of Fzo1p are regulated through degradation of Fzo1p by the F-box protein Mdm30p. How Mdm30p promotes degradation of Fzo1p is currently unknown. We have now determined that during vegetative growth Mdm30p mediates ubiquitylation of Fzo1p and that degradation of Fzo1p is an ubiquitin-proteasome–dependent process. In vivo, Mdm30p associates through its F-box motif with other core components of Skp1-Cullin-F-box (SCF) ubiquitin ligases. We show that the resulting SCFMdm30p ligase promotes ubiquitylation of Fzo1p at mitochondria and its subsequent degradation by the 26S proteasome. These results provide the first demonstration that a cytosolic ubiquitin ligase targets a critical regulatory molecule at the mitochondrial outer membrane. This study provides a framework for developing an understanding of the function of Mdm30p-mediated Fzo1p degradation in the multistep process of mitochondrial fusion.

scholarly journals GluA4 subunit of AMPA receptors mediates the early synaptic response to altered network activity in the developing hippocampus

2016 ◽  
Vol 115 (6) ◽  
pp. 2989-2996 ◽  
Author(s):  
J. Huupponen ◽  
T. Atanasova ◽  
T. Taira ◽  
S. E. Lauri
Keyword(s):  
Ampa Receptors ◽  
Pyramidal Neurons ◽  
Activity Patterns ◽  
Critical Role ◽  
Long Term Potentiation ◽  
Postnatal Period ◽  
Homeostatic Plasticity ◽  
Network Activity ◽  
Hippocampal Pyramidal Neurons ◽  
Activity Dependent

Development of the neuronal circuitry involves both Hebbian and homeostatic plasticity mechanisms that orchestrate activity-dependent refinement of the synaptic connectivity. AMPA receptor subunit GluA4 is expressed in hippocampal pyramidal neurons during early postnatal period and is critical for neonatal long-term potentiation; however, its role in homeostatic plasticity is unknown. Here we show that GluA4-dependent plasticity mechanisms allow immature synapses to promptly respond to alterations in network activity. In the neonatal CA3, the threshold for homeostatic plasticity is low, and a 15-h activity blockage with tetrodotoxin triggers homeostatic upregulation of glutamatergic transmission. On the other hand, attenuation of the correlated high-frequency bursting in the CA3-CA1 circuitry leads to weakening of AMPA transmission in CA1, thus reflecting a critical role for Hebbian synapse induction in the developing CA3-CA1. Both of these developmentally restricted forms of plasticity were absent in GluA4 −/− mice. These data suggest that GluA4 enables efficient homeostatic upscaling and responsiveness to temporal activity patterns during the critical period of activity-dependent refinement of the circuitry.

scholarly journals Individual Media Dependency, Social Media and Online Parenting Groups in Malaysia

2021 ◽  
Vol 23 (2) ◽  
pp. 1-16
Author(s):  
Cynthia Pui-Shan Lau ◽  
Hamedi Mohd Adnan ◽  
Amira Sariyati Firdaus
Keyword(s):  
New Media ◽  
Social Networking ◽  
Social Networking Sites ◽  
Network Activity ◽  
New Mothers ◽  
Media Dependency ◽  
Media Environment ◽  
Media Systems ◽  
The Individual ◽  
Interpersonal Network

This research paper examines new mothers’ dependency on parenting social networking sites particularly Facebook in Malaysia by adopting the Individual Media Dependency theory. Due to the ambiguity of the phenomena of transitioning into parenting for new mothers, it is apparent that new mothers rely on parenting social networking sites for support and information. This research is based on parenting social networking sites in Malaysia namely The Breastfeeding Advocates Network and The Parenting Network. Findings from this research suggests that social environment, media systems activity and interpersonal network activity are fundamental intervening conditions in today’s new media environment to fulfil an audience’s goal-oriented needs of orientation, understanding and play.

Spike Coding During Locomotor Network Activity in Ventrally Located Neurons in the Isolated Spinal Cord From Neonatal Rat

2000 ◽  
Vol 83 (5) ◽  
pp. 2825-2834 ◽  
Author(s):  
Morten Raastad ◽  
Ole Kiehn
Keyword(s):  
Spinal Cord ◽  
Locomotor Activity ◽  
Spike Trains ◽  
Neonatal Rat ◽  
Network Activity ◽  
Lumbar Spinal Cord ◽  
Patch Clamp Technique ◽  
Important Distinction ◽  
Spike Coding ◽  
The Individual

To characterize spike coding in spinal neurons during rhythmic locomotor activity, we recorded from individual cells in the lumbar spinal cord of neonatal rats by using the on-cell patch-clamp technique. Locomotor activity was induced by N-methyl-d aspartate (NMDA) and 5-hydroxytryptamine (5-HT) and monitored by ventral root recording. We made an estimator based on the assumption that the number of spikes arriving during two halves of the locomotor cycle could be a code used by the neuronal network to distinguish between the halves. This estimator, termed the spike contrast, was calculated as the difference between the number of spikes in the most and least active half of an average cycle. The root activity defined the individual cycles and the positions of the spikes were calculated relative to these cycles. By comparing the average spike contrast to the spike contrast in noncyclic, randomized spike trains we found that approximately one half the cells (19 of 42) contained a significant spike contrast, averaging 1.25 ± 0.23 (SE) spikes/cycle. The distribution of spike contrasts in the total population of cells was exponential, showing that weak modulation was more typical than strong modulation. To investigate if this low spike contrast was misleading because a higher spike contrast averaged out by occurring at different positions in the individual cycles we compared the spike contrast obtained from the average cycle to its maximal value in the individual cycles. The value was larger (3.13 ± 0.25 spikes) than the spike contrast in the average cycle but not larger than the spike contrast in the individual cycles of a random, noncyclic spike trains (3.21 ± 0.21 spikes). This result suggested that the important distinction between cyclic and noncyclic cells was only the repeated cycle position of the spike contrast and not its magnitude. Low spike frequencies (5.2 ± 0.82 spikes/cycle, that were on average 3.5 s long) and a minimal spike interval of 100–200 ms limited the spike contrast. The standard deviation (SD) of the spike contrast in the individual neurons was similar to the average spike contrasts and was probably stochastic because the SDs of the simulated, noncyclic spike trains were also similar. In conclusion we find a highly distributed and variable locomotor related cyclic signal that is represented in the individual neurons by very few spikes and that becomes significant only because the spike contrast is repeated at a preferred phase of the locomotor cycle.

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