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 towards
understanding how the interplay between the two processes effectuates synaptic
homeostasis. Here, we report that a co-dependence 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 post-synaptic 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.