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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...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2021
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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. |
format | Online Article Text |
id | pubmed-8610276 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
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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