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

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 betwee...

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Autores principales: Srinivasan, Balakumar, Samaddar, Sarbani, Mylavarapu, Sivaram V. S., Clement, James P., Banerjee, Sourav
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8610276/
https://www.ncbi.nlm.nih.gov/pubmed/34813590
http://dx.doi.org/10.1371/journal.pbio.3001432
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author Srinivasan, Balakumar
Samaddar, Sarbani
Mylavarapu, Sivaram V. S.
Clement, James P.
Banerjee, Sourav
author_facet Srinivasan, Balakumar
Samaddar, Sarbani
Mylavarapu, Sivaram V. S.
Clement, James P.
Banerjee, Sourav
author_sort Srinivasan, Balakumar
collection PubMed
description 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.
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spelling pubmed-86102762021-11-24 Homeostatic scaling is driven by a translation-dependent degradation axis that recruits miRISC remodeling Srinivasan, Balakumar Samaddar, Sarbani Mylavarapu, Sivaram V. S. Clement, James P. Banerjee, Sourav PLoS Biol Research Article 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. Public Library of Science 2021-11-23 /pmc/articles/PMC8610276/ /pubmed/34813590 http://dx.doi.org/10.1371/journal.pbio.3001432 Text en © 2021 Srinivasan et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Srinivasan, Balakumar
Samaddar, Sarbani
Mylavarapu, Sivaram V. S.
Clement, James P.
Banerjee, Sourav
Homeostatic scaling is driven by a translation-dependent degradation axis that recruits miRISC remodeling
title Homeostatic scaling is driven by a translation-dependent degradation axis that recruits miRISC remodeling
title_full Homeostatic scaling is driven by a translation-dependent degradation axis that recruits miRISC remodeling
title_fullStr Homeostatic scaling is driven by a translation-dependent degradation axis that recruits miRISC remodeling
title_full_unstemmed Homeostatic scaling is driven by a translation-dependent degradation axis that recruits miRISC remodeling
title_short Homeostatic scaling is driven by a translation-dependent degradation axis that recruits miRISC remodeling
title_sort homeostatic scaling is driven by a translation-dependent degradation axis that recruits mirisc remodeling
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8610276/
https://www.ncbi.nlm.nih.gov/pubmed/34813590
http://dx.doi.org/10.1371/journal.pbio.3001432
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