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.

p { margin-bottom: 0.25cm; direction: ltr; color: #00000a; line-height: 120%; text-align: left; orphans: 2; widows: 2 }p.western { font-family: "Liberation Serif", "Times New Roma", serif; font-size: 12pt; so-language: en-US }p.cjk { font-family: "Noto Sans CJK SC Regular", "Times"; font-size: 12pt }p.ctl { font-family: "FreeSans", "Times New Roman" }a.western:link { so-language: uz-Cyrl-UZ }a.ctl:link { so-language: uz-Cyrl-UZ }