Vectorial channeling as a mechanism for translational control by functional prions and condensates

Abstract

Significance Messenger RNA (mRNA)/protein assemblies such as functional prions and condensates are involved in locally regulating translation in eukaryotic cells. The mode of regulation depends on the structure of these assemblies. We show that the vectorial processive nature of translation can couple to transport via diffusion so as to repress or activate translation depending on the structure of the RNA protein assembly. We find that multiple factors including diffusivity changes and free energy biases in the assemblies can regulate the translation rate of mRNA by changing the balance between substrate recycling and competition between mRNAs. We mainly focus on the example of CPEB, a functional prion that has been implicated in the mechanism of synaptic plasticity of neurons and in memory. Translation of messenger RNA (mRNA) is regulated through a diverse set of RNA-binding proteins. A significant fraction of RNA-binding proteins contains prion-like domains which form functional prions. This raises the question of how prions can play a role in translational control. Local control of translation in dendritic spines by prions has been invoked in the mechanism of synaptic plasticity and memory. We show how channeling through diffusion and processive translation cooperate in highly ordered mRNA/prion aggregates as well as in less ordered mRNA/protein condensates depending on their substructure. We show that the direction of translational control, whether it is repressive or activating, depends on the polarity of the mRNA distribution in mRNA/prion assemblies which determines whether vectorial channeling can enhance recycling of ribosomes. Our model also addresses the effect of changes of substrate concentration in assemblies that have been suggested previously to explain translational control by assemblies through the introduction of a potential of mean force biasing diffusion of ribosomes inside the assemblies. The results from the model are compared with the experimental data on translational control by two functional RNA-binding prions, CPEB involved in memory and Rim4 involved in gametogenesis.