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:	Balakumar Srinivasan, Sarbani Samaddar, Sivaram V S Mylavarapu, James P Clement, Sourav Banerjee
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/62d02f7afe14424aa58079262c907e24
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spelling	oai:doaj.org-article:62d02f7afe14424aa58079262c907e242021-12-02T19:54:42ZHomeostatic scaling is driven by a translation-dependent degradation axis that recruits miRISC remodeling.1544-91731545-788510.1371/journal.pbio.3001432https://doaj.org/article/62d02f7afe14424aa58079262c907e242021-11-01T00:00:00Zhttps://doi.org/10.1371/journal.pbio.3001432https://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885Homeostatic 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.Balakumar SrinivasanSarbani SamaddarSivaram V S MylavarapuJames P ClementSourav BanerjeePublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 19, Iss 11, p e3001432 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Balakumar Srinivasan Sarbani Samaddar Sivaram V S Mylavarapu James P Clement Sourav Banerjee Homeostatic scaling is driven by a translation-dependent degradation axis that recruits miRISC remodeling.
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	article
author	Balakumar Srinivasan Sarbani Samaddar Sivaram V S Mylavarapu James P Clement Sourav Banerjee
author_facet	Balakumar Srinivasan Sarbani Samaddar Sivaram V S Mylavarapu James P Clement Sourav Banerjee
author_sort	Balakumar Srinivasan
title	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_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_sort	homeostatic scaling is driven by a translation-dependent degradation axis that recruits mirisc remodeling.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/62d02f7afe14424aa58079262c907e24
work_keys_str_mv	AT balakumarsrinivasan homeostaticscalingisdrivenbyatranslationdependentdegradationaxisthatrecruitsmiriscremodeling AT sarbanisamaddar homeostaticscalingisdrivenbyatranslationdependentdegradationaxisthatrecruitsmiriscremodeling AT sivaramvsmylavarapu homeostaticscalingisdrivenbyatranslationdependentdegradationaxisthatrecruitsmiriscremodeling AT jamespclement homeostaticscalingisdrivenbyatranslationdependentdegradationaxisthatrecruitsmiriscremodeling AT souravbanerjee homeostaticscalingisdrivenbyatranslationdependentdegradationaxisthatrecruitsmiriscremodeling
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Homeostatic scaling is driven by a translation-dependent degradation axis that recruits miRISC remodeling.

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